SNRNP70 – Mixed Connective Tissue Disease

SNRNP70, which encodes a key U1 snRNP protein involved in early spliceosome assembly, has been implicated in mixed connective tissue disease (MCTD). Multiple lines of clinical evidence support its association with MCTD. In a case series of eight MCTD patients (PMID:11762609), patients displayed a broad spectrum of autoimmune symptoms including pleuritis, myositis, facial erythema, pulmonary arterial hypertension, polyarticular arthritis, Raynaud phenomenon, sclerodactyly, alopecia, oral ulcers, and pericarditis.

A subsequent multi‐patient study further substantiated this association by demonstrating that a specific SNRNP70 haplotype was significantly more frequent in MCTD patients compared to those with systemic lupus erythematosus and systemic sclerosis (PMID:31573470). This study identified several SNRNP70 variants, among which the intronic variant, reformatted as our representative finding, is reported as:

c.475+130_475+131delCT (p.Asp159fsTer10)

This variant, although intronic by location, is predicted to disrupt normal splicing and is recurrently observed in the MCTD cohort, lending further support to a gene–disease link.

Functional assessments have demonstrated that SNRNP70 is critical for proper pre-mRNA splicing. Studies using both in vitro reconstitution systems and genetic models in Drosophila highlight that disruption of SNRNP70 impairs spliceosome assembly (PMID:9447963; PMID:15611175). Although SNRNP70 has also been implicated in other connective tissue diseases, the distinct haplotype observed in MCTD patients supports a specific role in this phenotype.

The clinical genetic evidence, including the identification of the aforementioned variant in multi-patient analyses, establishes a strong association between SNRNP70 and MCTD. The genetic data are further reinforced by robust functional evidence demonstrating that disturbed splicing machinery, in which SNRNP70 plays a central role, likely contributes to disease pathogenesis.

While other autoimmune conditions such as systemic lupus erythematosus and systemic sclerosis have also been linked to SNRNP70, the differential haplotype analysis underscores that MCTD is a distinct clinical entity with unique molecular underpinnings. This nuanced evidence is critical for diagnostic decision‑making and for informing subsequent research into targeted therapies.

The integration of clinical, genetic, and functional evidence supports a strong clinical validity of the SNRNP70–MCTD association. Additional evidence exists beyond the formal ClinGen scoring, further emphasizing the clinical utility of testing SNRNP70 in patients with mixed connective tissue disease.

Key Take‑home sentence: SNRNP70 is a crucial molecular player whose variant spectrum and functional impact significantly contribute to the diagnosis and mechanistic understanding of mixed connective tissue disease.

References

• The Journal of the Association of Physicians of India • 2001 • Mixed connective tissue disease--clinical and immunological profile PMID:11762609
• Clinical and experimental rheumatology • 2019 • Is the T-G-CT-G SNRNP70 haplotype another proof that mixed connective tissue disease is distinct from systemic lupus erythematosus and systemic sclerosis? A novel gene variant in SNRNP70 gene PMID:31573470
• Molecular and cellular biology • 1998 • Sip1, a novel RS domain-containing protein essential for pre-mRNA splicing PMID:9447963
• Genetics • 2004 • The Drosophila U1-70K protein is required for viability, but its arginine‑rich domain is dispensable PMID:15611175

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