Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Departments of Medicine (Cardiovascular Diseases), Pediatrics (Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
Gastroenterology. 2014 Jun;146(7):1659-1668. doi: 10.1053/j.gastro.2014.02.054. Epub 2014 Mar 5.
BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.
Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
SCN5A 基因编码电压门控钠离子通道 NaV1.5 的α亚基。许多由 SCN5A 基因突变引起的心律失常患者也有肠易激综合征（IBS）的症状。我们研究了 IBS 患者是否存在影响 NaV1.5 功能的 SCN5A 变体。
我们对 584 名 IBS 患者和 1380 名无 IBS（对照）患者的 SCN5A 进行了基因型分析。在人胚肾 293 细胞中表达 SCN5A 的突变形式，并通过电压钳分析评估其功能。对 SCN5A 基因的全基因组关联研究进行了分析，并在 4 个独立的 IBS 患者和对照患者队列中进行了 1745 名患者的复制。
在 584 名患者中发现了 SCN5A 的错义突变（13 例，2.2%，先证者）。腹泻为主型 IBS 是整个研究人群中最常见的 IBS 形式（25%）。然而，具有 SCN5A 突变的个体中更常见的是便秘为主型 IBS（31%）而不是腹泻为主型 IBS（10%；P<.05）。电生理分析表明，检测到的 13 种突变中有 10 种破坏了 NaV1.5 功能（9 种失活功能和 1 种失活功能）。p. A997T-NaV1.5 对降低 NaV1.5 功能的影响最大。用 mexiletine 孵育表达该变体的细胞可恢复其钠电流，对该突变的 1 名携带者（患有便秘为主型 IBS）给予 mexiletine 可使他的肠道习惯正常化。在全基因组关联研究和 4 项复制研究中，SCN5A 基因座与 IBS 强烈相关。
约 2%的 IBS 患者携带 SCN5A 基因突变。这些突变大多是失活突变，破坏了 NaV1.5 通道的功能。这些发现为 IBS 提供了一个新的致病机制和可能的治疗选择。
