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PreprintCited by 0Retinal Development and DisordersOcular Disorders and TreatmentsGenomics and Rare Diseases

Confirmation of the MIR204 n.37C>T heterozygous variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma

Open access
Jedlickova, J., Vajter, M., Barta, T., Black, G., Mares, J., Fichtl, M., Kousal, B., Dudakova, L. +1 more·2023·medRxiv
DOI 10.1101/2023.02.09.23284763
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Abstract

Four members of a three-generation family with early-onset chorioretinal dystrophy were shown to be heterozygous carriers of the n.37C>T in MIR204 . The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change in MIR204 . The chorioretinal dystrophy was variably associated with iris coloboma, congenital glaucoma, and premature cataracts extending the phenotypic range of the condition. In silico analysis of the n.37C>T variant revealed 713 novel targets. Additionally, family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants.

AI snapshot

Written from the paper’s full text.

TL;DR

This study confirms the heterozygous MIR204 n.37C>T variant as a cause of early-onset chorioretinal dystrophy variably associated with iris coloboma, congenital glaucoma, and premature cataracts in a three-generation family. In silico analysis suggests the variant alters miRNA seed sequence and target repertoire, consistent with a gain-of-function mechanism, while OCA2 variants explained co-occurring albinism in relatives.

Key findings

  • Four members across three generations had early-onset chorioretinal dystrophy and were heterozygous carriers of MIR204 n.37C>T; the variant was classified pathogenic according to ACMG criteria.
  • The phenotype was variable: iris coloboma was present in at least one eye of 3/4 carriers, congenital glaucoma occurred in the youngest daughter (not described in the previously published family), and early-onset cataracts were documented in the proband and his mother; the only constant sign was early-onset chorioretinal dystrophy.
  • In silico, n.37C>T hsa-miR-204-5p was predicted to target 2112 mRNAs versus 1114 for wild type, with 285 shared targets; the variant changed binding preferences for most shared targets and gained regulation of Wnt, insulin-like growth factor, and G-protein coupled glutamate receptor pathways while losing cell-cycle regulation.
  • Additional OCA2 findings included a compound heterozygous pathogenic missense variant c.1327G>A p.(Val443Ile) and a large complex rearrangement in the proband’s spouse; the oldest daughter had dual MIR204-associated chorioretinal dystrophy and oculocutaneous albinism, and two sons were homozygous for OCA2 c.1327G>A with normal visual acuity (1.0 both eyes) and foveal hypoplasia grade 1.

Methods

  • Clinical and genetic study of a three-generation family; ocular examination included BCVA, slit-lamp evaluation, fundoscopy, static automated perimetry, colour fundus photography, and SD-OCT, with foveal hypoplasia graded 1–4.
  • Exome sequencing was performed in individual III:4 and spouse II:3; genome sequencing was performed in the spouse; Sanger sequencing tracked segregation; rare variants were defined as minor allele frequency ≤0.001 in gnomAD, and pathogenicity was evaluated by ACMG/AMP recommendations.
  • miRNA target analysis used miRDB v6.0 for wild-type and n.37C>T hsa-miR-204-5p, DAVID for functional annotation, RNAfold for hairpin structure, and R/pheatmap for heatmap generation.

Limitations

  • The paper states that the precise molecular mechanism of MIR204-associated disease remains unknown and that it remains unclear how the intersection of MIR204 and OCA2 defects influences retinal morphology.
  • Evident from the text: the study is based on a single small family with four affected MIR204 variant carriers, limiting phenotypic and segregation inference.
  • Evident from the text: the target prediction and functional annotation findings are in silico and were not experimentally validated in this study.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1101/2023.02.09.23284763

Cites

22 of 22 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

15 of 18 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The MIR204 n.37C>T variant is a previously reported pathogenic variant.

    “The identification of this previously reported pathogenic variant confirms the existence of a distinct clinical entity caused by a sequence change in MIR204.”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Findingown data

    The MIR204 n.37C>T variant was classified as pathogenic according to ACMG criteria.

    “The variant was classified as pathogenic according to the ACMG criteria:”
    Quote in the paperSubstantial claim1 of 1 sources checked
  • Findingcitation

    The spouse of the proband is a compound heterozygote for the pathogenic missense variant c.1327G>A p.(Val443Ile) in OCA2 and a large complex pathogenic rearrangement.

    “The spouse of the proband was found to be a compound heterozygote for the pathogenic missense variant c.1327G>A p.(Val443Ile) in OCA2 (NM_000275.3) and a large complex pathogenic rearrangement, previously characterised in detail by Loftus et al. 14”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    The OCA2 structural variant is a 143 kb inverted segment reintroduced in intron 1 followed by an additional 184 kb deletion across the same region, restoring exons 3-19 of OCA2 to a copy-number neutral state.

    “In brief, a 143 kb inverted segment is reintroduced in intron 1 followed by an additional 184 kb deletion across the same region, restoring exons 3-19 of OCA2 to a copy-number neutral state.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    MIR204 is necessary for normal eye development including photoreceptor differentiation and function.

    “MIR204 is necessary for normal eye development including photoreceptor differentiation and function.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] source
    • cites [3] source
  • Classified as probably not a substantial claim. 15
  • May combine two claims. 20

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The MIR204 n.37C>T variant was previously found in 6 members from a five-generation family of white British descent, and the associated disease was termed RDICC.

    “Previously the n.37C>T variant, in the seed region of MIR204, was found in 6 members from a five-generation family of white British descent and the associated disease was termed “retinal dystrophy and iris coloboma with or without congenital cataract” (RDICC, MIM #616722).1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] source

      The Results describe a five-generation family of white British descent, and the mutation findings report MIR204 n.37C>T in six tested affected relatives. The paper describes retinal dystrophy and iris coloboma, with or without cataract, but our copy does not use the name RDICC or say it termed the disease that way. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The OCA2 structural variant has been repeatedly observed in compound heterozygosity with pathogenic variants in patients diagnosed with albinism.

    “The SV has been repeatedly observed in compound heterozygosity with pathogenic variants in patients diagnosed with albinism.14”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Morpholino-mediated knockdown of miR-204 in medaka fish resulted in microphthalmia, abnormal lens formation, and altered dorsoventral patterning of the retina with optic fissure coloboma.

    “Morpholino-mediated knockdown of miR-204 in medaka fish resulted in microphthalmia, abnormal lens formation, and altered dorsoventral patterning of the retina with optic fissure coloboma.1,3”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] source
    • cites [3] source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Pathogenicity of detected variants was evaluated according to ACMG and AMP recommendations.

    “The pathogenicity of the detected variants was evaluated according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology recommendations.6”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premiseown data

    The expression of both premiRNA and processed -3p/-5p forms of the MIR204 n.37C>T variant was not affected compared to wild type, suggesting the mutation does not alter premiRNA processing.

    “Notably, the expression of both premiRNA, as well as processed -3p/-5p forms of the MIR204 n.37C>T variant was not affected when compared to the wild type, suggesting that the mutation does not alter premiRNA processing. 1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] source

      In “The Effect of the n.37C > T Mutation on miRNA Target Recognition” (page not available), the paper reports that precursor miR-204 and mature miR-204 expression appeared largely unaffected by the variant compared with wild type, supporting the suggested lack of an effect on processing. The copy does not report separate expression measurements for the processed -3p and -5p forms, so that specific part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The pathogenic role of miRNAs may have been significantly underestimated and could explain part of the missing heritability.

    “In general, the pathogenic role of miRNAs may have been significantly underestimated and could explain part of the missing heritability.22”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] source

      The discussion on p. 2 says miRNA mutations can cause inherited retinal dystrophy and recommends screening for additional disease-causing mutations, supporting the possibility that their contribution has been overlooked. It does not discuss missing heritability or establish that the pathogenic role of miRNAs has been significantly underestimated in general. (LLM, conf=0.79)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    MIR204 belongs to the group of recently characterised retinal-specific miRNAs regulating important processes in the retina including phototransduction cascade and development of RPE, neural retina, ciliary body, and lens.

    “The MIR204 belongs to the group of recently characterised retinal-specific miRNAs 20,21 regulating important processes in the retina including phototransduction cascade and development of RPE, neural retina, ciliary body, and lens.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] source

      The 'miRNAs in the Developing Retina' table (page unavailable) lists miR-204 and associates it with retina and lens development. It does not identify miR-204 as retinal-specific or recently characterized, and it does not attribute phototransduction or development of the RPE and ciliary body specifically to miR-204. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [21] source

      The Results report miR-204 expression in mouse retina, enrichment in the inner nuclear layer, and increased levels in response to light. The cited paper does not establish that miR-204 is retina-specific or that it regulates phototransduction or development of the RPE, neural retina, ciliary body, or lens. Its identified photoreceptor-cell target is attributed to the different miR-183/96/182 cluster (Discussion). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Family members were affected by albinism resulting from biallelic pathogenic OCA2 variants.

    “Additionally, family members were shown to be affected by albinism resulting from biallelic pathogenic OCA2 variants.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Coloboma was not a constant sign, although present in at least one eye of three out of four individuals carrying the MIR204 n.37C>T variant.

    “Coloboma was not a constant sign, although it was present in at least one eye of three out of the four individuals carrying the n.37C>T in MIR204.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Segregation analysis revealed the proband is a heterozygous carrier of c.1327G>A in OCA2, which explained pseudodominance for albinism in this family.

    “Segregation analysis (Fig. 1) revealed that the proband is also a heterozygous carrier of the c.1327G>A variant in OCA2 which explained pseudodominance for albinism in this particular family.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The oldest daughter is a compound heterozygote for c.1327G>A inherited from the proband and the pathogenic OCA2 SV inherited from her mother, in addition to harbouring the MIR204 n.37C>T variant.

    “The oldest daughter was shown to be a compound heterozygote for the c.1327G>A inherited from the proband and the pathogenic OCA2 SV inherited from her mother, in addition to harbouring the n.37C>T in MIR204.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Another ocular condition running in the family was OCA2 presenting as oculocutaneous form in the spouse and in one offspring who had a dual diagnosis.

    “Another ocular condition running in the family was OCA2 presenting as oculocutaneous form in the spouse and in one of the offspring who had a dual diagnosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The daughter with dual diagnosis did not show atrophic lesions in the macula or RPE clumping.

    “Interestingly, she did not show atrophic lesions in the macula or RPE clumping.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Central macular atrophy surrounded with RPE resembling toxoplasmosis was observed in affected members.

    “Interestingly, we observed central macular atrophy surrounded with retinal pigment epithelium (RPE) resembling toxoplasmosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The mother of the proband (I:2) had bilateral retinal lesions considered as a sequela of retinal toxoplasmosis in the first decade of life.

    “The mother of the proband (individual I:2, Fig. 1) with no family history of ocular disease had bilateral retinal lesions, which were according to the available past medical records considered as a sequela of retinal toxoplasmosis in first decade of life.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The youngest daughter (III:4) suffered from congenital glaucoma and underwent several antiglaucoma procedures in both eyes.

    “The youngest one, in early school age at the time of clinical evaluation (individual III:4, Fig. 1), was noted to suffer from congenital glaucoma for which she had been treated elsewhere.She underwent several antiglaucoma procedures in both eyes (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The miRNA molecule carrying the MIR204 n.37C>T variant may target 2112 mRNAs, compared to 1114 mRNAs of the WT, with 285 genes shared.

    “The miRNA molecule carrying the pathogenic variant may target 2112 mRNAs, compared to 1114 mRNAs of the WT, with 285 genes shared (Fig. 4B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serial BCVA measurements in the proband showed gradual decline, with counting fingers in the right eye and light projection in the left eye in the third decade of life.

    “Serial measurements of BCVA showed gradual decline, with counting fingers in the right eye and light projection in the left eye in the third decade of life (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Fundus of III:1 was hypopigmented bilaterally but had no focal lesions or pigment deposits.

    “Fundus was hypopigmented bilaterally but there were no focal lesions or pigment deposits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Clinical evaluation of III:1 showed markedly low BCVA (0.04 right, 0.063 left) and advanced visual field constriction.

    “The clinical evaluation showed markedly low BCVA; 0.04 in the right eye and 0.063 in the left eye, and advanced visual field constriction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Two sons (III:2 and III:3) reported no visual symptoms and had uncorrected visual acuity 1.0 in both eyes.

    “Two sons of the proband, in the pre-teen and teenage years (individuals III:2 and III:3, Fig. 1), reported no visual symptoms and correspondingly their uncorrected visual acuity was 1.0 in both eyes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Two sons with OCA2 at molecular level presented with normal visual acuity, discrete fundus hypopigmentation and foveal hypoplasia.

    “Two sons shown to have OCA2 at molecular level presented with normal visual acuity, discrete fundus hypopigmentation and foveal hypoplasia, which was only revealed by chance due to familial investigation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    BCVA of III:4 was 0.06 and light projection in the right and left eye, respectively.

    “BCVA was 0.06 and light projection in the right and left eye, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Upon clinical examination in her 70s, individual I:2 was completely blind with no light perception, had cataract in the right eye, iris coloboma in the left eye, and advanced bilateral chorioretinal dystrophy.

    “Upon clinical examination performed in her 70s, the patient was completely blind with no light perception.There was also cataract in the right eye, iris coloboma in the left eye, and advanced bilateral chorioretinal dystrophy (Table 1, Fig. 2A-D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The two sons had discreet fundus hypopigmentation and SD-OCT showed bilateral foveal hypoplasia (grade 1).

    “There was a discreet fundus hypopigmentation and SD-OCT scans showed bilateral foveal hypoplasia (grade 1) in both children (Supplementary Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SD-OCT of III:1 revealed absent foveal pit/depression and chorioretinal atrophy.

    “SD-OCT revealed absent foveal pit/depression and chorioretinal atrophy (Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Examination of III:4 revealed bilateral macular atrophic lesions with pigmented edges, pale fundus bilaterally, no signs of premature cataracts, and band keratopathy in both eyes.

    “Our examination revealed bilateral macular atrophic lesions with pigmented edges.In addition, her fundus appeared pale bilaterally.There were no signs of premature cataracts.She also developed band keratopathy in both eyes (Fig. 2G, H).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The proband's cataract was described as congenital in available medical documentation.

    “The manifestation of cataract is unknown, however available medical documentation described it as congenital.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Functional annotation analysis suggests the MIR204 n.37C>T variant gains novel abilities to regulate crucial signalling pathways including canonical and non-canonical Wnt pathway, insulin-like growth factor pathway and G-protein coupled glutamate receptor pathway, while it loses the ability to directly regulate cell cycle via cell cycle-dependent protein kinases and cyclins.

    “The functional annotation analysis suggests that the n.37C>T variant gains novel abilities to regulate crucial signalling pathways including canonical and non-canonical Wnt pathway, insulin-like growth factor pathway and G-protein coupled glutamate receptor pathway, while it loses the ability to directly regulate cell cycle via cell cycle-dependent protein kinases and cyclins (Fig. 4D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The in silico target prediction and functional annotation analyses accurately reflect the functional consequences of the MIR204 n.37C>T variant.

  • May combine two claims.

    Findingown data

    The MIR204 n.37C>T variant shares multiple functional annotation clusters with the WT variant, but the number of target genes significantly differs.

    “Additionally, the n.37C>T variant shares multiple functional annotation clusters with the WT variant, however, the number of target genes significantly differs (Fig. 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The MIR204 n.37C>T variant introduces profound changes to preferential binding to mRNA targets and binds to novel mRNAs.

    “indicating that the n.37C>T variant not only introduces profound changes to preferential binding to mRNA targets but also binds to novel mRNAs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study was approved by the Ethical review board of General University Hospital in Prague.

    “The study followed the tenets of the Declaration of Helsinki and was approved by the Ethical review board of General University Hospital in Prague (reference number 412/20 S-IV).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All investigated subjects or their legal representatives provided informed consent.

    “All investigated subjects or their legal representatives provided informed consent with examination and publishing of the results prior to the inclusion into the study.”
    Quote in the paperNot a substantial claim
33 of 33

  • The paper relies on this without support.

    The in silico target prediction and functional annotation analyses accurately reflect the functional consequences of the MIR204 n.37C>T variant.

    “This scenario is largely supported by the miRNA target and functional annotation analyses performed in this study.”
1 of 1

Cites

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Related

Authors
Jedlickova, J., Vajter, M., Barta, T., Black, G., Mares, J., Fichtl, M., Kousal, B., Dudakova, L., & Liskova, P.
Affiliations
  • Charles University (CZ)
  • Manchester Royal Eye Hospital (GB)
ORCID
Venue
medRxiv
Publisher
openRxiv
Published
2023-02-11
DOI
10.1101/2023.02.09.23284763
OpenAlex
W4320033785
Semantic Scholar
6ff23d41b488cb304210421b5950841bd4328fde
Cited by
0
References
22
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
medRxiv (acceptedVersion, cc-by-nc)
Funders
  • Ministerstvo Školství, Mládeže a Tělovýchovy (825575, UNCE/MED/007)
  • Grantová Agentura České Republiky (VFN64165, GA21-08182S)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
chorioretinal dystrophy, iris coloboma, congenital glaucoma, early-onset cataract, albinism, heterozygous pathogenic variant, familial inheritance, in silico analysis

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