The DOI matches its Crossref record; 61 of the 65 references it cites were found in a registry or an index; 38 of the 54 sources its claims cite were checked for support.
Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
Open accessAbstract
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1–5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA–target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs. Clinical insights from patients with a rare genetic skeletal disorder led to the discovery of the first case of a pathogenic gain-of-function miRNA mutation.
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TL;DR
The paper reports a heterozygous neomorphic seed-region mutation in MIR140 (miR-140-5p) causing a novel autosomal dominant skeletal dysplasia, with mutant miRNA producing both loss- and gain-of-function effects. Mouse knock-in models recapitulate key skeletal abnormalities distinct from miR-140-null mice, and mutant miR-140-5p competes with Ybx1 at overlapping RNA binding sites.
Key findings
- The same heterozygous substitution, chr16:g.69967007A>G (MIR140:NR_029681.1:n.24A>G), was found in three affected individuals from two unrelated families; it occurred de novo in P1 and P3, co-segregated in Family 1, and was absent from gnomAD. Clinical features included disproportionate short stature, short limbs, small hands and feet, midface hypoplasia, mild spondylar dysplasia, delayed epiphyseal ossification, and severe brachydactyly with cone-shaped phalangeal epiphyses.
- CRISPR-Cas9 knock-in mice with the corresponding Mir140 A>G substitution showed delayed secondary ossification, decreased Col10a1 expression, delayed cartilage maturation of larynx/trachea/anterior ribs, severely decreased epiphyseal mineralization, mildly flat vertebral bodies, and a wider basal skull growth plate; these features were distinct from miR-140−/− mice.
- Small RNA sequencing showed the mutation yielded slightly greater mutant miR-140-5p than wild-type miR-140-5p and decreased two miR-140-3p species, without miRNA-processing defects. RNA-seq showed widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, including Loxl3, Btg1, and Trps1; the hypoxia pathway was impaired in miR-140G/G but not miR-140−/− chondrocytes, with reduced Hif1a and collagen crosslinking.
- Ago2 and Ybx1 seCLIP analyses indicated that the mutant miR-140-5p seed competes with Ybx1 for overlapping binding sites, especially in 3′ UTRs; Ybx1 inhibition dampened mutant miRNA-mediated repression. The authors describe this as the first case of a pathogenic gain-of-function miRNA mutation.
Methods
- Clinical and genetic study of two unrelated families: exome sequencing, whole genome sequencing, Sanger sequencing, and comparative genomic hybridization; the MIR140 variant was identified and confirmed in affected individuals.
- Mouse model: CRISPR-Cas9 knock-in of the Mir140 A>G substitution; heterozygous (miR-140G/+), homozygous (miR-140G/G), wild-type (miR-140+/+), and miR-140−/− mice were compared using skeletal preparations, histology, micro-CT, BrdU labeling, TUNEL staining, and collagen crosslink analysis.
- Molecular analyses in primary rib chondrocytes and cell lines: small RNA sequencing, RNA sequencing, qRT-PCR, Western blot, luciferase reporter assays, single-cell dual fluorescence reporter assays, Ago2 and Ybx1 seCLIP, TargetScan prediction, GSEA, and RBP motif analysis.
Limitations
- Stated: seCLIP had low sensitivity for small starting materials such as primary chondrocytes, and intronic seCLIP clusters were considered non-specific; sample sizes were estimated based on prior experience, with examined mouse numbers in Supplementary Table 2; human genome data are protected by Swedish law, with raw Sanger sequencing data available upon request.
- Evident: the human genetic evidence comes from only three affected individuals in two families, limiting broader genotype–phenotype generalization.
- Evident: much of the mechanistic evidence relies on mouse chondrocytes and heterologous cell assays, and the paper does not report an independent human cohort validating the proposed Ybx1 competition mechanism.
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Claims the paper makes
84 Own result · 28 Own interpretation · 10 Partly supported · 8 Supported · 8 Own method · 7 No basis given · 6 No full text of the sources · 3 Sources not found · 2 Couldn’t confirm · 1 Not checked yet · accuracy not yet measured
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“and is not reported in the gnomAD, a large scale human genome sequence database10”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Could not verifycites [10] Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016). sourceExperimental — accuracy not yet measured
The Article reSeArcH and ExAC data release sections describe a large human exome-variant database, but identify it as ExAC, not gnomAD. The substitution is not specified in the claim, and no passage in our copy establishes whether it is reported in gnomAD (searched: gnomAD, substitution, and database descriptions). (LLM, conf=0.74)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“This miR-140-null phenotype included mildly advanced terminal differentiation of growth plate chondrocytes of developing bones6,17.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [6] Nakamura, Y., Inloes, J. B., Katagiri, T. & Kobayashi, T. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol. Cell. Biol. 31, 3019–3028 (2011). source
In the section “Mir140-null mice show defects in endochondral bone growth,” the paper reports mild acceleration of chondrocyte differentiation. It also reports enlarged hypertrophic regions in developing talus and tibia bones, consistent with earlier terminal differentiation. (LLM, conf=0.91)
- Supportedcites [17] Papaioannou, G. et al. MicroRNA-140 provides robustness to the regulation of hypertrophic chondrocyte differentiation by the PTHrP-HDAC4 pathway. J. Bone Miner. Res. 30, 1044–1052 (2015). source
The Introduction states that miR-140 deficiency accelerates the differentiation of proliferating growth-plate chondrocytes into hypertrophic chondrocytes, while the overall effect is relatively mild. The Results also report accelerated chondrocyte hypertrophy in developing Mir140-null bones. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“loss of miR-140, encoded by Mir140, in mice leads to short stature and craniofacial abnormalities6,16”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [6] Nakamura, Y., Inloes, J. B., Katagiri, T. & Kobayashi, T. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol. Cell. Biol. 31, 3019–3028 (2011). source
The Abstract states that loss of Mir140 in mice results in dwarfism and craniofacial deformities. The section “Mir140-null mice show defects in endochondral bone growth” reports impaired growth, shorter long bones, and reduced longitudinal growth of the skull. No page numbers are provided in our copy. (LLM, conf=0.95)
- Supportedcites [16] Miyaki, S. et al. MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev. 24, 1173–1185 (2010). source
The 'Targeted deletion of cartilage-specific miR-140' section reports that mice lacking miR-140 developed short stature and craniofacial deformities after birth (Fig. 2B–E). It also confirms that miR-140 was absent in the knockout mice. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, previously reported YBX1-stabilized transcripts were preferentially repressed in miR-140G/G and miR-140G/+ chondrocytes as compared with miR-140−/− chondrocytes”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [34] Goodarzi, H. et al. Endogenous tRNA-derived fragments suppress breast cancer progression via ybx1 displacement. Cell 161, 790–802 (2015). source
The Results sections on competitive tRF binding and target-specific validation report YBX1-bound transcripts whose stability depends on YBX1, supporting the citation's identification of previously reported YBX1-stabilized transcripts. The comparison among miR-140 chondrocytes is the citing authors' finding, not a result attributed to this source. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“An extended search in copy number variation (CNV) databases regarding human phenotypes associated with CNVs involving the MIR140 gene revealed a single individual with heterozygous 1.1Mb deletion with isolated Arnold-Chiari malformation41.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Identification of the MIR140 mutation
What the sources say
- Could not verifycites [41] Kaminsky, E. B. et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13, 777–784 (2011). sourceExperimental — accuracy not yet measured
The Results section (CNV Characterization; page unavailable) describes aggregate CNV findings, not an individual with the claimed phenotype. Searches of our copy for MIR140, a 1.1 Mb deletion, and Arnold-Chiari malformation found no passage addressing the claimed case. (LLM, conf=0.76)
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This hypothesis is supported by the binding of YBX1 to several miR-140-5p-G target genes in a previously reported YBX1 individual nucleotide resolution crosslinking and immunoprecipitation (iCLIP) dataset”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Partly supportedcites [32] Wu, S. L. et al. Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme. Nucleic Acids Res. 43, 8516–8528 (2015). sourceExperimental — accuracy not yet measured
The Results ('Genome-wide mapping of YB-1-RNA interactions by iCLIP-seq'; page unavailable) identify this paper as a source of YBX1 iCLIP binding data, and the Discussion says its binding sites are enriched in coding genes. Our copy does not identify several miR-140-5p-G target genes as bound by YBX1, so it supports the dataset attribution but not that specific overlap. (LLM, conf=0.82)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The coding region of Hif1a that encodes a master transcription factor controlling hypoxic response27 contains a conserved sequence complementary to the miR-140-5p-G seed sequence.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [27] Wan, C. et al. Role of HIF-1α in skeletal development. Ann. N. Y. Acad. Sci. 1192, 322–326 (2010). source
Citation 27 is attached to the description of Hif1a as encoding a transcription factor that controls the hypoxic response, not to the sentence’s claim about a miR-140-5p-G seed match. The paper’s “hypoxia-inducible factor pathway” section describes HIF as a transcription factor that mediates adaptation to oxygen and identifies HIF-1α as a subunit. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Computational analysis suggested that the miR-140-5p-G seed in the Ago2 complex and the RBP, Ybx1 (also known as YB-1), potentially compete for the same RNA binding sites”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Could not verifycites [30] Ray, D. et al. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499, 172–177 (2013). sourceExperimental — accuracy not yet measured
The Large-scale analysis of RBPs section describes computational analysis of RBP binding motifs, but does not address competition between Ybx1 and an Ago2-bound microRNA. Searches for YBX1, miR-140-5p, and overlapping Ago2/RBP binding sites found no passage supporting the specific claim. (LLM, conf=0.76)
- Partly supportedcites [31] Wei, W. J. et al. YB-1 binds to CAUC motifs and stimulates exon inclusion by enhancing the recruitment of U2AF to weak polypyrimidine tracts. Nucleic Acids Res. 40, 8622–8636 (2012). sourceExperimental — accuracy not yet measured
The Results section (page unavailable) identifies CAUC and CACC as high-affinity RNA-binding motifs for YB-1, supporting the premise that YB-1 binds specific RNA sites. The paper does not report a miR-140-5p-G seed, an Ago2 complex, or computational evidence that either competes with YB-1 for the same sites. (LLM, conf=0.84)
- Could not verifycites [32] Wu, S. L. et al. Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme. Nucleic Acids Res. 43, 8516–8528 (2015). sourceExperimental — accuracy not yet measured
The Results section describes YB-1 binding to RNA and blocking DGCR8 and Dicer loading onto miR-29b-2 precursors. Our copy does not address computationally predicted competition between YB-1 and an Ago2-bound miR-140-5p-G seed for the same binding sites (searched: miR-140-5p-G, Ago2, and competition). (LLM, conf=0.76)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Partly supportedcites [22] Zhang, J. et al. Loss of lysyl oxidase-like 3 causes cleft palate and spinal deformity in mice. Hum. Mol. Genet. 24, 6174–6185 (2015). sourceExperimental — accuracy not yet measured
The Results section and the supplied Abstract (page not provided) show that loss of Loxl3 disrupts palate and vertebral development in mice, supporting its relevance to skeletal development. The paper does not identify Loxl3, Btg1, or Trps1 as miR-140-5p-G targets, or address the claimed metabolic-pathway targets; searches for those terms found no supporting passage. (LLM, conf=0.86)
- Partly supportedcites [23] Tijchon, E. et al. Targeted deletion of btg1 and btg2 results in homeotic transformation of the axial skeleton. PLoS ONE 10, e0131481 (2015). sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) says Btg1 and Btg2 play an important role in vertebral patterning, supporting Btg1’s relevance to skeletal development. The paper does not establish that Btg1, Loxl3, or Trps1 are miR-140-5p-G targets, or address the claimed metabolic-pathway targets. (LLM, conf=0.88)
- Partly supportedcites [24] Napierala, D. et al. Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome. Hum. Mol. Genet. 17, 2244–2254 (2008). sourceExperimental — accuracy not yet measured
The paper’s opening summary (p. 1) links Trps1 to skeletal dysplasia and bone development, supporting its identification as a gene important to the skeleton. Neither that passage nor the retrieved passages on Trps1 and Runx2 (pp. 5–6) identify miR-140-5p-G targets, Loxl3 or Btg1, or genes associated with metabolic pathways. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Furthermore, gene set enrichment analysis (GSEA) revealed that the hypoxia pathway is impaired in miR-140G/G, but not in miR-140−/− chondrocytes”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [25] Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005). source
The Abstract identifies this paper as the work that developed gene set enrichment analysis (GSEA), supporting its citation for the method used. The reported finding about miR-140 chondrocytes is the citing authors’ result, not a finding attributed to this source. (LLM, conf=0.90)
- Could not verifycites [26] Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5, e13984 (2010). sourceExperimental — accuracy not yet measured
The Materials and Methods section describes GSEA of breast-cancer-cell data, while the Results section discusses gene sets in early-onset colon cancer; no page numbers are available in our copy. Searches for miR-140 chondrocytes and hypoxia-pathway impairment found no passage addressing the claimed comparison between miR-140G/G and miR-140−/− chondrocytes. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
- Probably not a substantial claim. 36
- It may state two separate claims as one. 32
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1–5”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Mencia, A. et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat. Genet. 41, 609–613 (2009). source
- Partly supportedcites [2] Solda, G. et al. A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing. Hum. Mol. Genet. 21, 577–585 (2012). sourceExperimental — accuracy not yet measured
The Discussion reports a MIR96 point mutation that reduces mature miRNA levels and causes inherited hearing loss. It does not establish an association with several human congenital disorders: the affected family’s hearing loss began between ages 25 and 40, rather than being present at birth. (LLM, conf=0.90)
- Partly supportedcites [3] Hughes, A. E. et al. Mutation altering the miR-184 seed region causes familial keratoconus with cataract. Am. J. Hum. Genet. 89, 628–633 (2011). sourceExperimental — accuracy not yet measured
The main text (page unavailable) identifies a heterozygous point mutation in MIR184 associated with familial keratoconus and early-onset cataract, and reports that the mutant loses a tested miR-184 function. This supports an example within the multiply cited statement, but the paper does not establish that the affected individuals’ condition was congenital: it describes the cataract as early-onset. (LLM, conf=0.83)
- Partly supportedcites [4] Iliff, B. W., Riazuddin, S. A. & Gottsch, J. D. A single-base substitution in the seed region of miR-184 causes EDICT syndrome. Invest. Ophthalmol. Vis. Sci. 53, 348–353 (2012). sourceExperimental — accuracy not yet measured
The Results (page unavailable) identify a heterozygous single-base substitution in miR-184 that segregates with EDICT syndrome, which includes congenital cataract. The Discussion (page unavailable) proposes reduced miR-184 expression or activity as possible mechanisms but does not establish loss of function. This paper provides one example, not evidence for several congenital disorders. (LLM, conf=0.86)
- Partly supportedcites [5] Lechner, J. et al. Mutational analysis of MIR184 in sporadic keratoconus and myopia. Invest. Ophthalmol. Vis. Sci. 54, 5266–5272 (2013). sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) reports two heterozygous MIR184 substitutions in patients with keratoconus and shows that both reduced mature miR-184 expression; it also links a MIR184 mutation to EDICT syndrome, which includes congenital cataract. The Discussion (page unavailable) mentions MIR96 mutations associated with progressive hearing loss, but does not establish that heterozygous loss-of-function mutations across miRNA genes are associated with several congenital disorders. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Partly supportedcites [6] Nakamura, Y., Inloes, J. B., Katagiri, T. & Kobayashi, T. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol. Cell. Biol. 31, 3019–3028 (2011). sourceExperimental — accuracy not yet measured
The section ‘Mir140-null mice show defects in endochondral bone growth’ describes skeletal abnormalities in Mir140-null mice. But the paper describes a Mir140 deletion, not mice with the claimed single-nucleotide substitution; our copy does not report patient abnormalities or compare substitution-bearing mice with null mice. (LLM, conf=0.78)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Super-enhancers commonly drive high-level expression of tissue-specific genes, including miRNA genes, with evolutionarily conserved cell type-specific function11–13.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [11] Suzuki, H. I., Young, R. A. & Sharp, P. A. Super-enhancer-mediated RNA processing revealed by integrative microrna network analysis. Cell 168, 1000–1014 e1015 (2017). source
The Results section ‘Super-enhancers mark cell-type-specific and abundant miRNAs’ reports exceedingly high, cell-type-specific expression of super-enhancer-associated miRNAs. ‘Super-enhancer-miRNA network and evolution’ links their targets to tissue-characteristic functions and reports a tissue-dependent pattern suggesting co-evolution; the Introduction also describes the analysis of evolutionary conservation of miRNA networks. The Discussion characterizes super-enhancers more broadly as regulators of cell-identity genes. Page numbers are unavailable in our copy. (LLM, conf=0.86)
- Partly supportedcites [12] Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013). sourceExperimental — accuracy not yet measured
The Results sections on functional attributes and cell identity report higher expression of super-enhancer-associated genes, cell type-specific associations, and an ESC miRNA locus among those genes. The Discussion says these regulatory clusters evolved, but our copy does not establish that their cell type-specific functions are evolutionarily conserved. (LLM, conf=0.87)
- Partly supportedcites [13] Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013). sourceExperimental — accuracy not yet measured
The Results section reports that super-enhancers drive high-level expression of associated genes, and the Discussion says those genes tend to have cell type-specific expression and include miRNAs. Our copy does not establish that their cell type-specific function is evolutionarily conserved (pages not provided). (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“We observed that ceRBP effects are widespread in RNAi and contributes to off-target effects and phenotype modulation40.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [40] Suzuki, H. I., Spengler, R. M., Grigelioniene, G., Kobayashi, T. & Sharp, P. A. Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics. Nat. Genet. 50, 657–661 (2018). source
The Abstract states that seed-to-RBP crosstalk is widespread, contributes to off-target activity, and affects RNAi performance. It specifically reports widespread contributions to growth-phenotype modulation, supporting the citing sentence's paraphrase. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“YBX1 is a multifunctional RBP that stabilizes mRNAs and regulates RNA splicing33,34.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [33] Lyabin, D. N., Eliseeva, I. A. & Ovchinnikov, L. P. YB-1 protein: functions and regulation. Wiley Interdiscip. Rev. RNA 5, 95–110 (2014). source
- Partly supportedcites [34] Goodarzi, H. et al. Endogenous tRNA-derived fragments suppress breast cancer progression via ybx1 displacement. Cell 161, 790–802 (2015). sourceExperimental — accuracy not yet measured
The Results section describes YBX1 as a multifunctional RNA-binding protein, and the Introduction and Discussion say it stabilizes target transcripts. Our copy does not say that YBX1 regulates RNA splicing; a search for splicing found no supporting passage. Page numbers were not available in the indexed copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Next, Ybx1 seCLIP analysis identified a binding motif similar to the Ybx1 binding motif reported previously30–32”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Could not verifycites [30] Ray, D. et al. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499, 172–177 (2013). sourceExperimental — accuracy not yet measured
The Large-scale analysis of RBPs section describes how the paper derived RNA-binding motifs, but the passages found do not identify a YBX1 motif. Searches for “YBX1,” “YB-1,” and “Y-box binding protein 1” found no passage establishing the specific motif comparison attributed to this source. (LLM, conf=0.72)
- Supportedcites [31] Wei, W. J. et al. YB-1 binds to CAUC motifs and stimulates exon inclusion by enhancing the recruitment of U2AF to weak polypyrimidine tracts. Nucleic Acids Res. 40, 8622–8636 (2012). source
The Results section, “Defining the RNA-binding specificity of YB-1 by SELEX,” reports a YB-1 binding motif with CAUC and CACC variants. The citation supports the previously reported motif; the seCLIP finding is the citing authors’ own analysis, not a result attributed to this paper. (LLM, conf=0.92)
- Supportedcites [32] Wu, S. L. et al. Genome-wide analysis of YB-1-RNA interactions reveals a novel role of YB-1 in miRNA processing in glioblastoma multiforme. Nucleic Acids Res. 43, 8516–8528 (2015). source
The Results section (‘In vivo RNA binding specificity of YB-1’) reports a YB-1 binding consensus of UYAUC and says it closely resembles a previously determined in vitro SELEX motif. The cited paper used iCLIP, while seCLIP describes the citing authors’ analysis, not a method attributed to this source. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Besides gene dosage abnormalities37,38, single nucleotide substitutions in two miRNA genes have been identified in human diseases: MIR96 mutations in autosomal dominant deafness 50 (#613704) and MIR184 mutations in EDICT syndrome (#614303) and familial and sporadic cases of keratoconus1–5,39.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Mencia, A. et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat. Genet. 41, 609–613 (2009). source
- Partly supportedcites [2] Solda, G. et al. A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing. Hum. Mol. Genet. 21, 577–585 (2012). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [3] Hughes, A. E. et al. Mutation altering the miR-184 seed region causes familial keratoconus with cataract. Am. J. Hum. Genet. 89, 628–633 (2011). source
This paper is one of several citations attached to the MIR184 clause; its contribution is the familial keratoconus case. The paper’s opening summary reports a MIR184 seed-region mutation responsible for familial severe keratoconus with early-onset cataract (opening section; page unavailable). (LLM, conf=0.90)
- Partly supportedcites [4] Iliff, B. W., Riazuddin, S. A. & Gottsch, J. D. A single-base substitution in the seed region of miR-184 causes EDICT syndrome. Invest. Ophthalmol. Vis. Sci. 53, 348–353 (2012). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [5] Lechner, J. et al. Mutational analysis of MIR184 in sporadic keratoconus and myopia. Invest. Ophthalmol. Vis. Sci. 54, 5266–5272 (2013). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [39] Lewis, M. A. et al. An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat. Genet. 41, 614–618 (2009). sourceExperimental — accuracy not yet measured
The paper’s discussion reports two single-base changes in the miR-96 seed region in humans with progressive hearing loss, supporting the MIR96 portion of the claim. It does not identify autosomal dominant deafness 50 or address MIR184, EDICT syndrome, or keratoconus. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Gene regulation by conserved miRNAs has a significant impact on 3′ UTR evolution, and evolutionarily maintained target sites mediate actions of miRNAs more effectively than non-conserved target sites28.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Supportedcites [28] Grimson, A. et al. MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol. Cell 27, 91–105 (2007). source
The Introduction reports that more than 200 messages, on average, are under selective pressure to maintain sites for each highly conserved mammalian miRNA family, supporting an impact on 3′ UTR evolution. In the paper’s discussion of its quantitative efficacy model (page unavailable), conserved sites were somewhat more effective than nonconserved sites with the same score. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“miR-140-null mice were previously described6.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
What the sources say
- Supportedcites [6] Nakamura, Y., Inloes, J. B., Katagiri, T. & Kobayashi, T. Chondrocyte-specific microRNA-140 regulates endochondral bone development and targets Dnpep to modulate bone morphogenetic protein signaling. Mol. Cell. Biol. 31, 3019–3028 (2011). source
The section “Generation of Mir140-null mice” describes how the authors produced the mice. The section “Mir140-null mice show defects in endochondral bone growth” confirms that mice lacking Mir140 were generated by gene targeting. This paper therefore describes the mice identified by the citation. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mouse H3K27Ac and Sox9 ChIP-seq profiles were previously described51.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Super-enhancer analysis
What the sources say
- Supportedcites [51] Ohba, S., He, X., Hojo, H. & McMahon, A. P. Distinct transcriptional programs underlie Sox9 regulation of the mammalian chondrocyte. Cell Rep. 12, 229–243 (2015). source
The Results section (Identification of Sox9 Class I targets; page unavailable) describes ChIP-seq datasets from mouse rib chondrocytes and reports a Sox9 ChIP-seq profile. The Results section on Class II targets also describes H3K27Ac peaks flanking Sox9-bound regions, supporting the identification of the previously described profiles. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although miR-140G/G and miR-140−/− mice were smaller and had shorter noses than wild-type littermates”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Clinical features of the skeletal dysplasia included disproportionate short stature with short limbs, small hands and feet, and midface hypoplasia with small nose.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The radiological hallmarks were mild spondylar dysplasia, delayed epiphyseal ossification of the hip and knee, and severe brachydactyly with cone shaped phalangeal epiphyses”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The basal skull growth plate was wider due to the increased length of all layers of chondrocytes in miR-140G/G and miR-140G/+ mice, whereas miR-140−/− mice showed no significant changes”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“P1 and P2 also suffered from frequent respiratory infections with prolonged cough and inspiratory stridor.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All three affected individuals had normal intelligence, dentition, hearing, visual acuity, and basic blood tests.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“P1 had a narrow larynx likely due to floppy cartilage”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgedconditionalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Target sites of miR-140-5p-G seldom overlapped with those of wild-type miR-140 species (wild-type 5p, 3p.1, and 3p.2) and were less conserved than those of wild-type miR-140 species”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Out of 61 mice embryos injected with the guide RNA, repair template and Cas9, 11 mice were positive for the knock-in mutation.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
plainn = 11- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Screening P1, P2, and P3 for possible disease causing variants in 378 known skeletal dysplasia genes using WGS data, and screening P2 for gene dose abnormalities of the above mentioned skeletal dysplasia genes using custom-designed comparative genome hybridization analysis was all negative (data not shown), excluding involvement of these genes in the skeletal dysplasia phenotype of our patients.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Identification of the MIR140 mutation
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All of these mice were compound heterozygous with one allele mutated as desired and the other with various size insertion-deletion mutations.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
plainn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the miR-140 mutation found in this study affected the same nucleotide in both families and resulted in gain of a new function as well as loss of the original function, as shown by the transcriptome analysis revealing repression of new target genes and derepression of original targets.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suppressive effect of miR-140-5p-G is particularly strong for 8mer target sites (Extended Data Fig. 6b) and correlates with the predicted miRNA target efficiency”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A 3′ UTR reporter assay, using minimal target sequences and endogenous 3′ UTR sequences, confirmed that miR-140-5p-G and wild-type miR-140-5p target their respective predicted 8mer target sites with similar strengths, and validated the efficiency of target sites in several genes, respectively”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, genes with the identified 3′ UTR target sites of miR-140-5p-G were downregulated only in miR-140G/G and miR-140G/+ chondrocytes, while genes with wild-type miR-140-5p target sites were upregulated in both miR-140-null and miR-140 mutant chondrocytes”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“White arrow indicates apoptotic cells associated with blood vessels invaded into the epiphysis of wild type mice.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The right arytenoid cartilage is enlarged with redundant soft tissues and it prolapses antero-medially over the larynx during inspiration (a).”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“miR-140-5p-WT and miR-140-5p-G show similar and higher predicted target site efficiency than miR-140-3p.1 and miR-140-3p.2.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fiberscopy findings in P1, 44 years of age, consistent with laryngomalacia.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plaincorrelationalSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The second nucleotide in miR-140-5p is conserved from human to Australian ghostshark (indicated by a black arrow).”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The pathogenic variant in MIR140 (chr16:g.69967007A>G) (indicated by black arrows) in whole genome sequencing and exome sequencing data (left and right panels), and its Sanger sequencing confirmation (middle panel) in individuals P1, 2, and 3 as in Fig. 1.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Note that miR-140-5p and miR-140-3p are highly abundant miRNAs in chondrocytes, reflecting super-enhancer-mediated high transcriptional activity.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since we found no phenotypic differences between males and females, males and females were not discriminated for the analysis.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Skeletal preparation and histology
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“consistent with the increase in miR-140-5p and decrease in miR-140-3p in chondrocytes from miR-140G/+ and miR-140G/G mice.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“enrichment of miRNA motifs and Ybx1 motifs was not observed in intronic clusters (Extended Data Fig. 9b and 10b)”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > seCLIP analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Mutations in approximately 400 different genes are currently known to cause congenital skeletal diseases9”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [9] Bonafe, L. et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am. J. Med. Genet. A 167A, 2869–2892 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that the A>G mutation did not compromise miRNA processing and yielded abundant expression of miR-140-5p-G from primary miR-140 transcripts of which transcription is strongly activated by a super-enhancer in chondrocytes.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and are highly consistent with the skeletal dysplasia features of the patients, presenting with delayed secondary ossification, mild platyspondyly, small epiphyses, and scaphocephaly.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that the mutation produces both loss-of-function and gain-of-function effects.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these differences in phenotype between miR-140G/G and miR-140−/− mice, and delayed epiphyseal maturation in humans, indicate that this single-base substitution causes a neomorphic, and not just loss-of-function, effect.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, these mutations, occurring at multiple different nucleotides of single miRNAs, are thought to primarily cause loss of function”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“the disease phenotype may be at least partially explained by potential competition with the RBP, Ybx1, and by the super-enhancer-driven high-level miRNA expression”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“a neomorphic mutant miRNA would need to target a biologically important regulatory network in order to produce a disease phenotype.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“multiple RNA binding proteins (RBPs) are reported to modulate miRNA function29”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [29] van Kouwenhove, M., Kedde, M. & Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat. Rev. Cancer 11, 644–656 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, the present study expands our knowledge on how mutations in miRNAs contribute to human disease development”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that miR-140-5p exerts greater target repression than miR-140-3p even though the latter is more abundant.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In addition, given the expansion of miRNA genes in vertebrates7,8, the molecular mechanism revealed in this present study also has broader implications in understanding how function of new miRNA genes might evolve in humans.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [7] Chen, K. & Rajewsky, N. The evolution of gene regulation by transcription factors and microRNAs. Nat. Rev. Genet. 8, 93–103 (2007). source
- Not checked — no full text of the sourcecites [8] Berezikov, E. Evolution of microRNA diversity and regulation in animals. Nat. Rev. Genet. 12, 846–860 (2011). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“She had normal bone density for the age, which suggests that the heterozygous MIR140 mutation in humans does not lead to bone mass abnormalities.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Clinical diagnosis of spondyloepiphyseal dysplasia (SED) MIR140 type Nishimura
hedgedSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“This substitution creates a novel restriction enzyme site (Msp I; CCGG).”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sample size was estimated based on our prior experience of similar sets of experiments.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Luciferase reporter assay
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“HEK293T cells are tested for mycoplasma contamination.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Luciferase reporter assay
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Micro-CT analysis was performed in a blinded manner with all mice assigned to coded sample numbers.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Micro-CT analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that miR-140-5p-G follows mechanisms of conventional miRNA targeting as well as other endogenous miRNAs.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Note that miR-140-5p and miR-140-3p are highly abundant miRNAs in chondrocytes, reflecting super-enhancer-mediated high transcriptional activity.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The sample size was estimated based on our prior experience of performing similar sets of experiments and the number of examined mice is shown in Supplemental Table 2.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“After confirming the absence of additional mutations in the 2 kb region surrounding the Mir140 gene using Sanger sequencing”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
plainn = 5- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Each experiment included non-transfection controls.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Single-cell dual fluorescence reporter assay
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Selection of a single mature miRNA strand from miRNA duplex is determined by combination of 5′-end nucleotide identity and thermodynamic asymmetry of miRNA duplex termini (Ref. 20).”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Extended Data
What the sources say
- Not matchedcites Ref. 20
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The PCR amplicon containing the A>G substitution is digested into 98 bp and 119 bp long fragments.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Mice
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We independently repeated the molecular biology experiment at least twice, and all attempts to reproduce the results were successful.”
- Also stated in: § Statistical analysis · plain
“In molecular biology experiments, results are representative of more than two independent and reproducible experiments.”
§ Gain-of-function mutation of microRNA-140 in human skeletal dysplasia > Methods > Luciferase reporter assay
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Statistical analysis · plain
The paper relies on this without support.
Neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported.
“but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported.”
The paper relies on this without support.
Underlying molecular mechanisms are not elucidated for many congenital skeletal diseases.
“but underlying molecular mechanisms are not elucidated for many of them.”
The paper relies on this without support.
A mutation in the miRNA seed region creates a new repertoire of target genes and the magnitude of such target suppression is typically small.
“Since a mutation in the miRNA seed region creates a new repertoire of target genes and the magnitude of such target suppression is typically small”
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Cited by
Sorted by citations
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“A detailed understanding of the specific targets and molecular pathways disrupted by such mutations is essential for developing targeted therapies for skeletal dysplasia disorders [36,37].”
BackgroundFine Regulation of MicroRNAs in Gene Regulatory Networks and Pathophysiology
Seida, M., Ogami, K., Yoshino, S., & Suzuki, H. I. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072861 · Cited by 25
“…and serve as key regulators In addition to miRNAs, RNA-binding proteins (RBPs) interact with mRNAs and serve as key regulators of gene expression [91,92]. sequence motifs, miRNAs can sequester the RBPs, leading to the modulation of RBP activity When RBPs and miRNAs recognize the same sequence…”
InfluentialSelf-citationSNHG16 Silencing Inhibits Neuroblastoma Progression by Downregulating HOXA7 via Sponging miR-128-3p
Bao, J., Zhang, S., Meng, Q., et al. (2020) · Neurochemical Research · doi:10.1007/s11064-020-02955-x · Cited by 20
MicroRNAs in cartilage development and dysplasia
Shvedova, M., & Kobayashi, T. (2020) · Bone · doi:10.1016/j.bone.2020.115564 · Cited by 21
“Patients in a Swedish pedigree and an unrelated case in Israel were found to have the same clinical features and an identical single nucleotide substitution (A > G) at the second nucleotide of the miR-140–5p-coding sequence (the first nucleotide of the seed) [11].”
BackgroundInfluentialSelf-citationChaudhry, N., Muhammad, H., Seidl, C., Downes, D., Young, D., Hao, Y., Zhu, L.-Y., & Vincent, T. (2022) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2022.01.005 · Cited by 18
“As mutations affecting miR-140 have also been linked to skeletal abnormalities in humans 23 , these studies indicate that miR-140 plays an important homeostatic and chondroprotective role in the developing skeleton and adult joint. miRs can be targeted for therapeutic gain and can themselves be…”
de Carvalho, J. B., de Morais, G. L., Vieira, T. C. D. S., Rabelo, N. C., Llerena, J. C., Gonzalez, S., & de Vasconcelos, A. T. R. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01144 · Cited by 17
Critical role of cellular microRNAs in virus infection: Decades of progress
Han, Y., Zhang, G., Lv, X., & Ren, L. (2025) · Animals and zoonoses. · doi:10.1016/j.azn.2025.01.002 · Cited by 16
Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis
Kitai, H., Kato, N., Ogami, K., Komatsu, S., Watanabe, Y., Yoshino, S., Koshi, E., Tsubota, S., Funahashi, Y., Maeda, T., et al. (2022) · BMC Biology · doi:10.1186/s12915-022-01447-4 · Cited by 15
“Sequence analysis was performed according to the previous reports [9, 62, 65, 66].”
BackgroundMethodSelf-citationNew gene discoveries in skeletal diseases with short stature
Costantini, A., Muurinen, M., & Mäkitie, O. (2021) · Endocrine Connections · doi:10.1530/ec-21-0083 · Cited by 16
Reversing the miRNA -5p/-3p stoichiometry reveals physiological roles and targets of miR-140 miRNAs
Young, C., Caffrey, M., Janton, C., & Kobayashi, T. (2022) · RNA · doi:10.1261/rna.079013.121 · Cited by 13
“…nucleotide of the seed sequence, i.e. the second nucleotide, of miR-140-5p caused a novel skeletal dysplasia and showed that the equivalent mutation in mice causes a delay in chondrocytes maturation in the epiphysis due to an expansion of resting zone chondrocytes (Grigelioniene et al. 2019) (Fig.”
BackgroundMethodResultInfluentialSelf-citationLandscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer
Hua, X., Li, Y., Pentaparthi, S. R., McGrail, D. J., Zou, R., Guo, L., Shrawat, A., Cirillo, K. M., Li, Q., Bhat, A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-20-0371 · Cited by 14
“Beyond cancer, a gain-of-function mutation in miRNA-140 drastically altered its mRNA target profile, contributing to pathogenesis in human skeletal dysplasia (6).”
BackgroundmiR-345-5p regulates adipogenesis via targeting VEGF-B
Liu, X., He, Y., Feng, Z., Sheng, J., Dong, A., Zhang, M., & Cao, L. (2020) · Aging · doi:10.18632/aging.103649 · Cited by 13
Systematics for types and effects of RNA variations
Vihinen, M. (2020) · RNA Biology · doi:10.1080/15476286.2020.1817266 · Cited by 14
“‘VariO:0492 short non-coding RNA’ molecules are shorter than 200 nucleotides, often substantially shorter than the threshold. miR-140 which contains variants in skeletal dysplasia miRNA [77] is a short non-coding RNA.”
BackgroundInfluentialReyes, M., Firat, D., Hanna, P., Khan, M., Bruce, M., Shvedova, M., Kobayashi, T., Schipani, E., Gardella, T. J., & Jüppner, H. (2023) · JBMR Plus · doi:10.1002/jbm4.10802 · Cited by 12
“To replace histidine (His) at position 223 with arginine (Arg), improved genome editing via Oviductal Nucleic Acids Delivery (i-GONAD) (28 – 30) was performed approximately 16 h after coitus on wild-type (WT) females (CD1) that had been mated with a male homozygous for the WT-PTH1R (C57BL6/CD1…”
MethodSelf-citationGenetics of Skeletal Disorders
Hannan, F. M., Newey, P. J., Whyte, M. P., & Thakker, R. V. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_350 · Cited by 12
Yao, W., Kulyar, M. F., Ding, Y., Du, H., Hong, J., Loon, K. S., Nawaz, S., & Li, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310975 · Cited by 13
“Unlike miR-140-null mice, mice with identical single nucleotide mutations had skeletal deformities [30].”
BackgroundYao, Q., Parvez-Khan, M., & Schipani, E. (2020) · Bone · doi:10.1016/j.bone.2020.115572 · Cited by 12
Noncoding RNAs in skeletal development and disorders
Yao, Q., He, T., Liao, J., Liao, R., Wu, X., Lin, L., & Xiao, G. (2024) · Biological Research · doi:10.1186/s40659-024-00497-y · Cited by 11
“…generate a gain of functions of miR-140-5p and to be associated with autosomal dominant human skeletal dysplasia characterized by disproportionate short stature with smaller limbs, which is the first reported human disease caused by the gain-of-function mutations in a highly conserved miRNA [101].”
BackgroundLuo, Y., Li, Y., Peng, H., et al. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.11852 · Cited by 11
Villegas-Mirón, P., Gallego, A., Bertranpetit, J., Laayouni, H., & Espinosa‐Parrilla, Y. (2022) · Human Genetics · doi:10.1007/s00439-021-02423-8 · Cited by 11
“…in pathogenic processes (Sethupathy and Collins 2008; Rawlings-Goss et al. 2014; Torruella-Loran et al. 2016, 2019; Ghanbari et al. 2017a, b; Grigelioniene et al. 2019), but also be the origin of genetic innovations responsible for phenotypic adaptations (Lopez-Valenzuela et al. 2012; Lu et…”
BackgroundJedličková, J., Vajter, M., Bárta, T., Black, G. C. M., Perveen, R., Mareš, J., Fichtl, M., Kousal, B., Ďuďáková, Ľ., & Lišková, P. (2023) · Clinical Genetics · doi:10.1111/cge.14391 · Cited by 10
“To date, four have been identified as a cause of human disease.(26,27) Conte et al implicated a point variant in miRNA in inherited retinal dystrophy.”
BackgroundTang, Y., Wang, L.-Y., Chang, C.-M., Lee, I.-W., Tsai, W., & Sun, H. S. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.00897 · Cited by 9
Growth disorders caused by variants in epigenetic regulators: progress and prospects
Lui, J. C. K. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1327378 · Cited by 8
miRNA-based regulation in growth plate cartilage: mechanisms, targets, and therapeutic potential
Thakore, P., & Delany, A. M. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1530374 · Cited by 9
Construction of a serum diagnostic signature based on m5C-related miRNAs for cancer detection
Tang, F., Liu, Y., Sun, Y., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1099703 · Cited by 8
Transcriptional, epigenetic and microRNA regulation of growth plate
Nakamichi, R., Kurimoto, R., Tabata, Y., & Asahara, H. (2020) · Bone · doi:10.1016/j.bone.2020.115434 · Cited by 9
Kawano, S., Araki, K., Bai, J., Furukawa, I., Tateishi, K., Yoshinobu, K., Usuki, S., Nimmo, R. A., Kaname, T., Yoshihara, M., et al. (2023) · Cancer Science · doi:10.1111/cas.15794 · Cited by 6
Systematics for types and effects of DNA variations
Vihinen, M. (2018) · BMC Genomics · doi:10.1186/s12864-018-5262-0 · Cited by 8
Liu, J., Ning, C., Zhang, J., Xu, S., Wu, J., Tao, C., Ma, F., Chen, Q., & Pan, Z. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1338411 · Cited by 6
Brusati, A., Ratti, A., Pensato, V., Peverelli, S., Gentilini, D., Bella, E. D., Sorce, M. N., Meneri, M., Gagliardi, D., Corti, S. P., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1055313 · Cited by 6
“In this context, analysis of genetic variants in non-coding elements such as miRNAs and long noncoding RNAs (lncRNAs) has so far received poor attention in the field of complex diseases, while mutations in miRNAs proved to be causative of some hereditary disorders, such as spondyloepiphyseal dysplasia (Grigelioniene e…”
BackgroundSystems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesisPreprint
Patel, K., Barter, M. J., Soul, J., et al. (2023) · eLife · doi:10.7554/elife.89701 · Cited by 5
“Deletion of miR-140 in both humans and mice affects skeletal development ( Miyaki et al., 2010 ; Grigelioniene et al., 2019 ).”
BackgroundThe Growing Significance of microRNAs in Osteoporosis
Sarkar, A., Sarkar, S., Anwar, A., Kim, J. W., Shim, J., & John, A. A. (2025) · Cells · doi:10.3390/cells14231905 · Cited by 5
Wachs, A. S., & Bohne, J. (2020) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1616 · Cited by 4
“The first example of a gain-of-function mutation for a miRNA was reported in 2019 by Grigelioniene et al. (2019).”
BackgroundDistinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma
Enokido, T., Horie, M., Yoshino, S., Suzuki, H. I., Matsuki, R., Brunnström, H., Micke, P., Nagase, T., Saito, A., & Miyashita, N. (2023) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-23-0229 · Cited by 3
Self-citationGiovannetti, A., Bianco, S. D., Traversa, A., Panzironi, N., Bruselles, A., Lazzari, S., Liorni, N., Tartaglia, M., Carella, M., Pizzuti, A., et al. (2022) · Human Mutation · doi:10.1002/humu.24399 · Cited by 3
“…SNVs, which generally have a higher deleterious effect, is in accordance with this hypothesis and was demonstrated in several cases of both monogenic (Grigelioniene et al., 2019; Mencía et al., 2009) and complex traits (Duan et al., 2014; Reichenstein et al., 2019; Williams et al., 2019).”
BackgroundResultThe profiles of miR-4510 expression level in breast cancer
Majed, S. O., & Mustafa, S. A. (2023) · Scientific Reports · doi:10.1038/s41598-022-25292-1 · Cited by 3
Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis
Patel, K., Barter, M. J., Soul, J., et al. (2024) · eLife · doi:10.7554/elife.89701.4 · Cited by 3
Secondary ossification center induces and protects growth plate structure
Xie, M., Herdina, A. N., Estefa, J., Medvedeva, E. V., Li, L., Newton, P. T., Kotova, S., Shavkuta, B. S., Saxena, A., Shumate, L. T., et al. (2021) · Yearbook of pediatric endocrinology · doi:10.1530/ey.18.5.16 · Cited by 3
Zhang, Y.-F., Li, X., Cao, X., Ji, C., Gao, X.-Y., Gao, D., Han, H., Yu, F., & Zheng, M. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.866020 · Cited by 2
“Neural progenitors and differentiated neural cells migrate from the germinal zones guided by radial glia cells (RGCs) to reach the mantle layers, and form the cerebral cortex (Hansen et al., 2010; Franco et al., 2012; Kwan et al., 2012).”
BackgroundReduced glycolysis links resting zone chondrocyte proliferation in the growth platePreprint
Kobayashi, T., Young, C., Zhou, W., & Rhee, E. P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.18.524550 · Cited by 3
Self-citationXu, Y., Cheng, X., Zhang, M., Guo, J., Ren, K., Zhou, K., Li, T., Wang, Y., Li, Q., Meng, T., et al. (2025) · Cellular Signalling · doi:10.1016/j.cellsig.2025.112160 · Cited by 2
miRNA gene mutations commonly disrupt the proper functioning of miRNA genes
Machowska, M., Szóstak, N., Tire, A., Wegorek, W., Suszyńska, M., Kajdasz, A., Galka-Marciniak, P., Philips, A., & Kozłowski, P. (2026) · Science Advances · doi:10.1126/sciadv.aea6079 · Cited by 2
“…miRNA gene mutations have been implicated in Mendelian diseases, including mutations in MIR96 in nonsyndromic hearing loss ( 11 ), mutations in MIR184 in different hereditary eye diseases ( 12 ), mutations in MIR204 in retinal dystrophy ( 13 ), and mutations in MIR140 in skeletal dysplasia ( 14 ).”
Konopka, T., Vestito, L., & Smedley, D. P. (2021) · Bioinformatics Advances · doi:10.1093/bioadv/vbab026 · Cited by 2
Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy
Costa, M. A., Sadan, A. N., Bhattacharyya, N., Chai, N., Zarouchlioti, C., Liu, S., Szabó, A., Murphy, C., Ďuďáková, Ľ., Muthusamy, K., et al. (2025) · Genetics in Medicine · doi:10.1016/j.gim.2025.101562 · Cited by 3
Lindstrand, A., Lagerstedt‐Robinson, K., Jemt, A., Kvarnung, M., Ygberg, S. E., Vonlanthen, S., Oscarson, M., Nilsson, D., Lesko, N., Mantero, A. S., et al. (2026) · Genome Medicine · doi:10.1186/s13073-026-01611-3 · Cited by 1
“Beyond clinical utility, the infrastructure we built for clinical diagnostics has also supported multiple gene-discovery projects, which are described in separate publications [43–55].”
Self-citationmiR-514a promotes neuronal development in human iPSC-derived neurons
Akaba, Y., Takahashi, S., Suzuki, K., et al. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1096463 · Cited by 1
“The gainof-function mutation in miR-140 leads to the repression of mutant miR-140 targets through abundant expression of mutant miR-140 without defects in miRNA processing, leading to human skeletal dysplasia (Grigelioniene et al., 2019).”
BackgroundQian, F., Chen, X., Wang, S., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-69523-z · Cited by 1
“The pathogenic phenotypes of the functionally acquired by miRNA mutation are derived from human miR140 mutation, which was similarly proved in miR140-deficient mice 21 .”
Thakore, P., Smith, S. S., Karki, S., et al. (2025) · Journal of Bone and Mineral Research · doi:10.1093/jbmr/zjaf182 · Cited by 1
“23 These cases demonstrate how even subtle alterations in miRNA sequence or dosage can disrupt cartilage homeostasis and skeletal growth, reinforcing the critical role of noncoding RNAs in skeletal disease. miR-433-3p (miR-433) has been implicated in skeletal dysplasia through its interaction with…”
Jedlickova, J., Vajter, M., Barta, T., Black, G., Mares, J., Fichtl, M., Kousal, B., Dudakova, L., & Liskova, P. (2023) · doi:10.1101/2023.02.09.23284763
“312 Changes in seed sequence, which is essential for the miRNA binding to the target 313 mRNA, may lead to binding disruption and/or alterations to premiRNA processing.(16,17) 314 Notably, the expression of both premiRNA, as well as processed -3p/-5p forms of the MIR204 315 n.”
BackgroundMajed, S. O., & Mustafa, S. A. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3761839
Villegas-Mirón, P., Gallego, A., Bertranpetit, J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.24.445417
Reversing the miRNA -5p/-3p stoichiometry reveals physiological roles and targets of miR-140 miRNAsPreprint
Cameron, Y., Caffrey, M., Janton, C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.12.463698
Self-citationGao, M., Wang, Y., Liu, C., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1450575/v1
zou, H., zou, H., Zou, H., et al. (2020) · doi:10.21203/rs.3.rs-39817/v1
“Page 3/23 miRNAs are a class of small non-coding RNA of approximately 20 nucleotides in size and can suppress the expression of multiple target genes through post-transcriptional regulation [8,9].”
BackgroundData from Landscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer
Hua, X., Li, Y., Pentaparthi, S. R., McGrail, D. J., Zou, R., Guo, L., Shrawat, A., Cirillo, K. M., Li, Q., Bhat, A., et al. (2023) · doi:10.1158/0008-5472.c.6513646.v1
Data from Landscape of MicroRNA Regulatory Network Architecture and Functional Rerouting in Cancer
Hua, X., Li, Y., Pentaparthi, S. R., McGrail, D. J., Zou, R., Guo, L., Shrawat, A., Cirillo, K. M., Li, Q., Bhat, A., et al. (2023) · doi:10.1158/0008-5472.c.6513646
Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesisPreprint
Patel, K., Barter, M., Soul, J., et al. (2024) · eLife · doi:10.7554/elife.89701.3
The Interplay Between MicroRNAs and Genetic Diseases
Kushwaha, S., George, A., Kaur, H., Elangovan, A., Muthukumar, S., Iyer, M., Yadav, M., Parkash, J., Venkatesan, D., & Vellingiri, B. (2024) · Epigenetics and human health · doi:10.1007/978-3-031-64788-8_5
Spondyloepiphyseal dysplasias in the structure of idiopathic stunting in children
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Fine-tuning the growth plate by miRNA
Ono, N. (2025) · Journal of Bone and Mineral Research · doi:10.1093/jbmr/zjaf191
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Self-citationStranneheim, H., Lagerstedt‐Robinson, K., Magnusson, M., Kvarnung, M., Nilsson, D., Lesko, N., Engvall, M., Anderlid, B.-M., Arnell, H., Johansson, C. B., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14228410
Self-citationThe hypoxia signaling pathway in the skeleton
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Caractérisation de nouveaux gènes de prédisposition aux cancers du rein familiaux
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Metadata
- Authors
- Grigelioniene, G., Suzuki, H. I., Taylan, F., Mirzamohammadi, F., Borochowitz, Z. U., Ayturk, U. M., Tzur, S., Horemuzova, E., Lindstrand, A., Weis, M. A., Grigelionis, G., Hammarsjö, A., Marsk, E., Nordgren, A., Nordenskjöld, M., Eyre, D. R., Warman, M. L., Nishimura, G., Sharp, P. A., & Kobayashi, T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Karolinska Institutet (SE)
- Harvard University (US)
- Technion – Israel Institute of Technology (IL)
- Boston Children's Hospital (US)
- Rambam Health Care Campus (IL)
- Karolinska University Hospital (SE)
- University of Washington (US)
- Saitama Medical University Hospital (JP)
- Corresponding author
- Kobayashi, Tatsuya
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-02-25
- Volume
- 25
- Issue
- 4
- Pages
- 583-590
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6622181
- OpenAlex
- W2917129046
- Semantic Scholar
- dffcad30f105f92c7952744d74b10b64d6c8ec7f
- Cited by
- 103
- References
- 65
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 10 · 2023: 18 · 2022: 15 · 2021: 13 · 2020: 22 · 2019: 8
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Funders
- Eli Lilly and Company
- Massachusetts Institute of Technology (P30-CA14051)
- Dana-Farber Cancer Institute
- Uehara Memorial Foundation (NIH P30)
- European Society for Paediatric Endocrinology
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051)
- Karolinska Institutet
- Stockholms Läns Landsting (20150143)
- Vetenskapsrådet (2018-03046, 2018-)
- Svenska Läkaresällskapet
- Stiftelsen Samariten
- Science for Life Laboratory
- National Institutes of Health (P30-AR066261, GM034277, AR066261, R01-GM034277)
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Cancer Institute (P01 CA 042063, R01CA133404, CA14051, P30CA014051, P30-CA-14051)
- National Institute of General Medical Sciences (R01 GM034277)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR066261, R01AR056645)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- microRNA-140, gain-of-function mutations, neomorphic mutations, skeletal dysplasia, chondrocytes, YB-1, post-transcriptional regulation, super-enhancers, mouse model
- MeSH terms
- Gain of Function Mutation, Animals, Base Sequence, Bone Diseases, Developmental, Female, Homozygote, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Pedigree, Phenotype, Chondrocytes, MicroRNAs, Transcriptome
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