Mutant Neurogenin-3 in congenital malabsorptive diarrhea
Mutant Neurogenin-3 in congenital malabsorptive diarrhea
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DOI：
10.1056/nejmoa054288
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发表时间：
2006-07-20
影响因子：
158.5
通讯作者：
Martin, Martin G.
中科院分区：
文献类型：
--
作者：
Wang, Jiafang;Cortina, Galen;Martin, Martin G.
背景资料：神经生成素-3（NEUROG 3）在内分泌祖细胞中表达，是胰腺和肠内分泌细胞发育所必需的。因此，NEUROG 3基因（NEUROG 3）是一个新发现的常染色体隐性遗传疾病的原因的候选人，其特征是广泛的吸收不良和缺乏肠内分泌cells.Methods：我们筛选基因组DNA从三个不相关的患者稀疏肠内分泌细胞的NEUROG 3突变。然后，我们测试所观察到的突变改变NEUROG 3功能的能力，使用在体外和体内assays.Results：患者有几个肠道肠内分泌细胞阳性嗜铬粒蛋白A，但他们有正常数量的潘氏，杯状和吸收细胞。我们在NEUROG 3中鉴定了两个纯合突变，这两个突变都使NEUROG 3蛋白不能激活NEUROD 1（NEUROG 3的下游靶点），并损害了NEUROG 3与NEUROD 1启动子中的E-box元件结合的能力。注射野生型，但不是突变的NEUROG 3信使RNA到非洲爪蟾胚胎诱导NEUROD 1 expression.Conclusions：一个新发现的疾病，其特征是吸收不良性腹泻和缺乏肠道肠内分泌细胞是由NEUROG 3的功能丧失突变。
Background: Neurogenin-3 (NEUROG3) is expressed in endocrine progenitor cells and is required for endocrine-cell development in the pancreas and intestine. The NEUROG3 gene (NEUROG3) is therefore a candidate for the cause of a newly discovered autosomal recessive disorder characterized by generalized malabsorption and a paucity of enteroendocrine cells.Methods: We screened genomic DNA from three unrelated patients with sparse enteroendocrine cells for mutations of NEUROG3. We then tested the ability of the observed mutations to alter NEUROG3 function, using in vitro and in vivo assays.Results: The patients had few intestinal enteroendocrine cells positive for chromogranin A, but they had normal numbers of Paneth's, goblet, and absorptive cells. We identified two homozygous mutations in NEUROG3, both of which rendered the NEUROG3 protein unable to activate NEUROD1, a downstream target of NEUROG3, and compromised the ability of NEUROG3 to bind to an E-box element in the NEUROD1 promoter. The injection of wild-type but not mutant NEUROG3 messenger RNA into xenopus embryos induced NEUROD1 expression.Conclusions: A newly discovered disorder characterized by malabsorptive diarrhea and a lack of intestinal enteroendocrine cells is caused by loss-of-function mutations in NEUROG3.