ArticleHuman mutation2015
Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1.
Article in Human mutation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Identification and functional validation of a novel disease-causing variant in the noncoding region of NYX.Acta ophthalmologica · 2026Article
- Article
- SARM1: The Checkpoint of Axonal Degeneration in the Nervous System Disorders.Molecular neurobiology · 2025Review
- Non-coding single-nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Exploring non-coding variants and evaluation of antisense oligonucleotides for splicing redirection in Usher syndrome.Molecular therapy. Nucleic acids · 2024Article
- Programmed axon death: a promising target for treating retinal and optic nerve disorders.Eye (London, England) · 2024Review
- Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease.Genome medicine · 2024Article
- Systematic assessment of the contribution of structural variants to inherited retinal diseases.Human molecular genetics · 2023Article
- Multidisciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies.Human molecular genetics · 2023Article
- Clinical features and genetic spectrum of NMNAT1-associated retinal degeneration.Eye (London, England) · 2022Article
- Nuclear NADeLife · 2021Article
- Next-Generation Sequencing Applications for Inherited Retinal Diseases.International journal of molecular sciences · 2021Review
- New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of theInternational journal of molecular sciences · 2021Article
- SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration.eLife · 2020Article
- Gene Therapy Preserves Retinal Structure and Function in a Mouse Model ofMolecular therapy. Methods & clinical development · 2020Article
- Roles of Nmnat1 in the survival of retinal progenitors through the regulation of pro-apoptotic gene expression via histone acetylation.Cell death & disease · 2018Article
- Molecular Diagnosis of 34 Japanese Families with Leber Congenital Amaurosis Using Targeted Next Generation Sequencing.Scientific reports · 2018Article
- Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- Accuracy of Next-Generation Sequencing for Molecular Diagnosis in Patients With Infantile Nystagmus Syndrome.JAMA ophthalmology · 2017Article
- Toward an elucidation of the molecular genetics of inherited retinal degenerations.Human molecular genetics · 2017Review
Corrections and comments
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Authors and funding
15 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness.
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