Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.
Elife. 2019 Oct 30;8:e49910. doi: 10.7554/eLife.49910.
Inflammatory bowel disease (IBD) affects 1.5-3.0 million people in the United States. IBD is genetically determined and many common risk alleles have been identified. Yet, a large proportion of genetic predisposition remains unexplained. In this study, we report the identification of an ultr arare missense variant (NM_006998.3:c.230G > A;p.Arg77His) in the gene causing Mendelian early-onset ulcerative colitis. encodes a calcium sensor that is exclusively expressed in neuroendocrine lineages, including enteroendocrine cells and gut neurons. SCGN interacts with the SNARE complex, which is required for vesicle fusion with the plasma membrane. We show that the mutation identified impacted the localization of the SNARE complex partner, SNAP25, leading to impaired hormone release. Finally, we show that mouse models of deficiency recapitulate impaired hormone release and susceptibility to DSS-induced colitis. Altogether, these studies demonstrate that functional deficiency in SCGN can result in intestinal inflammation and implicates the neuroendocrine cellular compartment in IBD.
炎症性肠病（IBD）影响美国 150 万至 300 万人。IBD 是由基因决定的，许多常见的风险等位基因已经被确定。然而，很大一部分遗传易感性仍然无法解释。在这项研究中，我们报告了一种超罕见错义变异（NM_006998.3:c.230G > A;p.Arg77His）的鉴定，该变异位于基因中，导致孟德尔早发性溃疡性结肠炎。编码一种钙传感器，仅在神经内分泌谱系中表达，包括肠内分泌细胞和肠道神经元。SCGN 与 SNARE 复合物相互作用，该复合物对于囊泡与质膜融合是必需的。我们表明，鉴定出的 突变影响了 SNARE 复合物伴侣 SNAP25 的定位，导致激素释放受损。最后，我们表明， 缺乏的小鼠模型重现了激素释放受损和对 DSS 诱导的结肠炎的易感性。总之，这些研究表明，SCGN 的功能缺陷可导致肠道炎症，并提示神经内分泌细胞在 IBD 中的作用。
