MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma
Open accessAbstract
Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37 C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37 C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.
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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”
From Confirmation of the <i>MIR204</i> n.37C>T heterozygous variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma (2023) · cites this paper as [1]
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 measuredThe 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”
From Confirmation of the <i>MIR204</i> n.37C>T heterozygous variant as a cause of chorioretinal dystrophy variably associated with iris coloboma, early-onset cataracts and congenital glaucoma (2023) · cites this paper as [1]
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 measuredThe 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.”
MIR204 is necessary for normal eye development including photoreceptor differentiation and function.
“MIR204 is necessary for normal eye development including photoreceptor differentiation and function.”
Exome sequencing showed the youngest daughter (III:4) is a heterozygous carrier of the MIR204 n.37C>T variant.
“Exome sequencing showed that the youngest daughter of the proband (individual III:4, Fig. 1) is a heterozygous carrier of the n.37C>T in MIR204 (NR_029621.1), which has been previously reported in one family.1”
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”
Injection of the MIR204 n.37C>T variant into medaka fish embryo leads to severe ocular malformations including retinal dystrophy.
“Additionally, injection of the n.37C>T MIR204 variant into medaka fish embryo leads to severe ocular malformations including retinal dystrophy.1”
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Sorted by citations
Mutation-independent therapies for retinal diseases: focus on gene-based approaches
Carrella, S., Indrieri, A., Franco, B., & Banfi, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.588234 · Cited by 14 · see citing works
Self-citationJedlickova, 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
“Morpholino-mediated knockdown of miR-204 in medaka fish 67 resulted in microphthalmia, abnormal lens formation, and altered dorsoventral patterning of the 68 retina with optic fissure coloboma.(1,3) 69 In this study, we report a three-generation family with the occurrence of early-onset 70”
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- Authors
- Conte, I., Hadfield, K. D., Barbato, S., Carrella, S., Pizzo, M., Bhat, R. S., Carissimo, A., Karali, M., Porter, L. F., Urquhart, J., Hateley, S., O’Sullivan, J., Manson, F. D. C., Neuhauss, S. C. F., Banfi, S., & Black, G. C. M.
- Affiliations
- Telethon Institute of Genetics and Medicine, Pozzuoli 80078, Italy;
- University of Manchester (GB)
- Telethon Institute Of Genetics And Medicine (IT)
- National Health Service (GB)
- University of Zurich (CH)
- University of Campania "Luigi Vanvitelli" (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-06-08
- Volume
- 112
- Issue
- 25
- Pages
- E3236-45
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4485104
- OpenAlex
- W1894704888
- Cited by
- 115
- References
- 3
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 14 · 2023: 10 · 2022: 8 · 2021: 9 · 2020: 16 · 2019: 10 · 2018: 7 · 2017: 11 · 2016: 10 · 2015: 5
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute for Health and Care Research (BRF-2011-015, NF-SI-0509-10185, CL-2015-07-004)
- 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 › Cancer Research › MicroRNA in disease regulation
- Keywords
- miR-204, inherited retinal disease, coloboma, autosomal dominant inheritance, photoreceptor apoptosis, rod and cone photoreceptors, retinal development, retinal pigment epithelium, gain-of-function mutations, hereditary blindness
- MeSH terms
- Base Sequence, Coloboma, Female, Humans, Genetic Linkage, Male, Pedigree, Sequence Homology, Nucleic Acid, MicroRNAs, Retinal Dystrophies, Exome
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