Faculty, Staff and Student Publications

Language

English

Publication Date

1-1-2026

Journal

Nature Genetics

DOI

10.1038/s41588-025-02451-4

PMID

41513982

PMCID

PMC12807869

PubMedCentral® Posted Date

1-9-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.

Keywords

Retinitis Pigmentosa, RNA, Small Nuclear, Humans, Male, Female, Genes, Dominant, Pedigree, Ribonucleoproteins, Small Nuclear, Ribonucleoprotein, U4-U6 Small Nuclear, Mutation, Spliceosomes, Diseases, Medical genetics

Published Open-Access

yes

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