Familial Diarrhea Syndrome Caused by an Activating GUCY2C Mutation
Familial Diarrhea Syndrome Caused by an Activating GUCY2C Mutation
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DOI：
10.1056/nejmoa1110132
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发表时间：
2012-04-26
影响因子：
158.5
通讯作者：
Knappskog, Per M.
中科院分区：
文献类型：
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作者：
Fiskerstrand, Torunn;Arshad, Najla;Knappskog, Per M.
家族性腹泻疾病在大多数情况下是严重的，由隐性突变引起。我们描述了一个挪威家庭的32名成员的一种新的显性疾病的原因。受影响的成员有慢性腹泻，是早期发病，是相对温和的，并与增加的易感性，炎症性肠病，小肠梗阻，和esophagitis. METHODS我们使用连锁分析，基于阵列与单核苷酸多态性，以确定一个候选区域的染色体12，然后测序GUCY 2C，编码鸟苷酸环化酶C（GC-C），细菌热稳定肠毒素的肠受体。我们对三个受影响的家庭成员的整个候选区域进行了外显子组测序，以排除GUCY 2C以外的基因突变可能导致或有助于对疾病的易感性。我们使用HEK 293 T细胞对突变型GC-C进行了功能研究。我们在所有受影响的家族成员中鉴定了GUCY 2C中的杂合错义突变（c.2519G -> T），并且在候选区域的基因外显子中没有观察到其他罕见的变体。突变体受体暴露于其配体导致环磷酸鸟苷（cGMP）的产生显着增加。这可能会导致过度激活的囊性纤维化跨膜调节因子（CFTR），导致增加氯化物和水的分泌从肠上皮细胞，并因此可能解释慢性腹泻在受影响的家庭members.CONCLUSIONSIncreased GC-C信号干扰正常的肠功能，似乎有一个促炎作用，无论是通过增加氯化物分泌或额外的影响升高细胞cGMP。需要进一步研究影响GC-C-CFTR通路的遗传变异与克罗恩病等疾病的相关性。（由Helse Vest [挪威西部地区卫生局]和印度政府科学技术部资助。
BACKGROUNDFamilial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis.METHODSWe used linkage analysis, based on arrays with single-nucleotide polymorphisms, to identify a candidate region on chromosome 12 and then sequenced GUCY2C, encoding guanylate cyclase C (GC-C), an intestinal receptor for bacterial heat-stable enterotoxins. We performed exome sequencing of the entire candidate region from three affected family members, to exclude the possibility that mutations in genes other than GUCY2C could cause or contribute to susceptibility to the disease. We carried out functional studies of mutant GC-C using HEK293T cells.RESULTSWe identified a heterozygous missense mutation (c.2519G -> T) in GUCY2C in all affected family members and observed no other rare variants in the exons of genes in the candidate region. Exposure of the mutant receptor to its ligands resulted in markedly increased production of cyclic guanosine monophosphate (cGMP). This may cause hyperactivation of the cystic fibrosis transmembrane regulator (CFTR), leading to increased chloride and water secretion from the enterocytes, and may thus explain the chronic diarrhea in the affected family members.CONCLUSIONSIncreased GC-C signaling disturbs normal bowel function and appears to have a proinflammatory effect, either through increased chloride secretion or additional effects of elevated cellular cGMP. Further investigation of the relevance of genetic variants affecting the GC-C-CFTR pathway to conditions such as Crohn's disease is warranted. (Funded by Helse Vest [Western Norway Regional Health Authority] and the Department of Science and Technology, Government of India.)