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Cystic fibrosis (CF) is an autosomal recessive disorder caused by biallelic mutations in CFTR, yet phenotypic variability suggests modifying loci. Syntaxin 1A (STX1A) encodes a SNARE protein that negatively regulates CFTR gating and surface expression, making it a candidate CF modifier (MONDO:0009061; HGNC:11433).
In a discovery cohort of CF patients from the Bernese CF Registry, STX1A intronic variant rs4363087 (c.467-38A>G) significantly associated with lung function metrics by linear mixed model analysis (PMID:23572023). The risk allele effect replicated in the European CF Twin and Sibling Study (P = 0.0027) (PMID:23572023). Genetic association across two independent cohorts supports a modifier role rather than monogenic causation.
rs4363087 is in strong linkage disequilibrium with synonymous exonic variant rs2228607 (c.204C>T). Although not altering the protein sequence, c.204C>T enhances aberrant splicing of STX1A pre-mRNA, triggering nonsense-mediated decay and reducing STX1A transcript levels (PMID:23572023). This functional consequence aligns with decreased negative regulation of CFTR and a milder lung phenotype.
Biochemical studies further demonstrate that STX1A directly interacts with CFTR and other epithelial ion channels, modulating their surface expression and gating properties (PMID:10990372). Reduced STX1A levels may therefore relieve inhibition of residual CFTR function, improving chloride transport in airway epithelia.
No conflicting studies have challenged the modifier effect of STX1A in CF. Together, replicated genotype-phenotype correlations and molecular mechanism data constitute moderate clinical validity and functional evidence for STX1A as a CF modifier.
Key take-home: STX1A c.467-38A>G (rs4363087) is a replicated genetic modifier of CF lung disease via aberrant mRNA splicing, with potential utility for prognostic stratification.
Gene–Disease AssociationModerateModifier effect supported by genotype-phenotype association in two independent CF cohorts and functional splicing data Genetic EvidenceModeraters4363087 (c.467-38A>G) associated with lung function in Bernese registry and replicated in European CF Twin and Sibling Study; variant in LD with c.204C>T Functional EvidenceModerateSynonymous variant c.204C>T induces aberrant splicing and NMD, reducing STX1A transcripts and modulating CFTR regulation |