SNTA1 – Long QT Syndrome

Alpha-1-syntrophin (SNTA1) is a scaffolding protein that links neuronal nitric oxide synthase (nNOS) and the plasma membrane Ca-ATPase PMCA4b to the cardiac sodium channel Nav1.5. Heterozygous missense variants in SNTA1 have been reported in individuals with autosomal dominant long QT syndrome (LQTS), a disorder characterized by prolonged cardiac repolarization and risk of syncope, arrhythmia, seizures, and sudden death.

Genetic screening identified a recurrent SNTA1 variant c.770C>G (p.Ala257Gly) in three unrelated probands presenting with prolonged QTc and syncope ([PMID:19684871]). Segregation was limited: only one carrier had a family history of LQTS, and no multi-generation co-segregation was documented. Additional rare SNTA1 missense variants (p.Ala390Val, p.Glu363Ala) have been reported in single LQTS and drug-induced LQTS cases, but none have demonstrated robust segregation or loss-of-function evidence.

Functional studies consistently show that pathogenic SNTA1 variants perturb Nav1.5 gating through an nNOS-dependent gain-of-function mechanism. In HEK293 and neonatal rat cardiomyocytes, p.Ala257Gly and p.Ala390Val increase peak and late sodium currents and shift activation voltage dependence ([PMID:19684871]; [PMID:18591664]). Three additional SIDS-associated SNTA1 mutations (p.Ser287Arg, p.Thr262Pro, p.Gly460Ser) also increase late INa and are reversible by nNOS inhibition ([PMID:20009079]).

Modifier studies demonstrate intragenic rescue: the SNTA1 polymorphism p.Pro74Leu reverses the increased INa caused by p.Ala257Gly in heterologous systems, highlighting complexity in genotype–phenotype correlations ([PMID:24319568]). Digenic interactions between SNTA1 p.Ala261Val and SCN5A p.Arg800Leu further enhance late INa, supporting additive effects in LQTS pathogenesis ([PMID:23376825]).

A recent evidence-based reappraisal classified SNTA1 as having limited to disputed causal evidence for typical LQTS, citing a paucity of segregation data and reliance on functional assays in the absence of larger cohorts ([PMID:31983240]). Thus, SNTA1 variants alone should be interpreted cautiously in diagnostic settings and ideally corroborated by electrophysiological characterization.

In summary, heterozygous SNTA1 missense variants are associated with a gain-of-function in Nav1.5 and can contribute to LQTS risk, but current evidence is limited by small case numbers and minimal familial segregation. Functional assays support a disease mechanism via nNOS-mediated channel modulation. Key take-home: SNTA1 variant interpretation requires integration of functional data and careful genetic counselling for clinical decision-making.

References

• Circulation. Arrhythmia and electrophysiology • 2008 • alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. PMID:19684871
• Proceedings of the National Academy of Sciences of the United States of America • 2008 • Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. PMID:18591664
• Circulation. Arrhythmia and electrophysiology • 2009 • Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current. PMID:20009079
• American journal of physiology. Heart and circulatory physiology • 2013 • Digenic inheritance novel mutations in SCN5a and SNTA1 increase late I(Na) contributing to LQT syndrome. PMID:23376825
• Cardiogenetics • 2011 • LQTS-associated mutation A257G in α1-syntrophin interacts with the intragenic variant P74L to modify its biophysical phenotype. PMID:24319568
• Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240

Evidence Based Scoring (AI generated)