Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5%-10% of SIDS may stem from cardiac channelopathies like long QT syndrome (LQTS). We recently implicated mutations in α1-syntrophin (SNTA1) as a novel cause of LQTS, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase (nNOS) by the plasma membrane Ca-ATPase PMCA4b causing increased peak and late sodium current (INa) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations.
Methods and Results
Using PCR, DHPLC, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M and G460S) were identified in 8 (~3%) out of 292 SIDS cases. These mutations were engineered using PCR-based overlap-extension and were co-expressed heterologously with SCN5A, nNOS and PMCA4b in HEK293 cells. INa was recorded using the whole-cell method. A significant 1.4-1.5 fold increase in peak INa and 2.3-2.7 fold increase in late INa compared with controls was evident for S287R-, T372M-, and G460S-SNTA1, and was reversed by an nNOS inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation thereby increasing the overlap of the activation and inactivation curves to increase window current.
Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins like α1-syntrophin from similarly rare but innocuous ones.
Keywords: death, sudden, long-QT syndrome, genetics, ion channels, nitric oxide synthase