Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI, USA.
Circ Arrhythm Electrophysiol. 2009 Dec;2(6):667-76. doi: 10.1161/CIRCEP.109.891440.
Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in alpha1-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (I(Na)) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations.
Using polymerase chain reaction, denaturing high-performance liquid chromatography, 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 (approximately 3%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction-based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells. I(Na) was recorded using the whole-cell method. A significant 1.4- to 1.5-fold increase in peak I(Na) and 2.3- to 2.7-fold increase in late I(Na) compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase 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 such as alpha1-syntrophin from similarly rare but innocuous ones.
婴儿猝死综合征（SIDS）是出生后 6 个月内死亡的主要原因。大约 5%至 10%的 SIDS 可能源于心脏通道病，如长 QT 综合征。我们最近发现，α1- 连接蛋白（SNTA1）的突变是长 QT 综合征的一个新原因，突变的 SNTA1 通过质膜 Ca-ATP 酶 PMCA4b 释放对相关神经元型一氧化氮合酶的抑制作用，导致通过心脏钠通道的 S-亚硝基化增加峰和晚期钠电流（I（Na））。本研究确定了与 SIDS 相关的 SNTA1 突变的患病率和功能特性。
使用聚合酶链反应、变性高效液相色谱法和 SNTA1 开放阅读框的 DNA 测序，在 292 例 SIDS 病例中的 8 例（约 3%）中发现了 6 种罕见（800 个参考等位基因中不存在）错义突变（G54R、P56S、T262P、S287R、T372M 和 G460S）。这些突变是使用基于聚合酶链反应的重叠延伸技术设计的，并与 SCN5A、神经元型一氧化氮合酶和 PMCA4b 一起在 HEK293 细胞中异源表达。使用全细胞方法记录 I（Na）。与对照组相比，S287R、T372M 和 G460S-SNTA1 的峰 I（Na）增加了 1.4 至 1.5 倍，晚期 I（Na）增加了 2.3 至 2.7 倍，并且神经元型一氧化氮合酶抑制剂可逆转这些变化。这 3 种突变还导致通道失活的明显去极化偏移，从而增加激活和失活曲线的重叠以增加窗口电流。
异常的生物物理表型表明，SNTA1 突变是心脏通道病 SIDS 亚组的一种新的致病机制。功能研究对于区分通道相互作用蛋白（如α1-连接蛋白）的致病干扰与类似但无害的罕见突变至关重要。
