Höglund P, Haila S, Socha J, Tomaszewski L, Saarialho-Kere U, Karjalainen-Lindsberg M L, Airola K, Holmberg C, de la Chapelle A, Kere J
Department of Medical Genetics, Haartman Institute, Helsinki, Finland.
Nat Genet. 1996 Nov;14(3):316-9. doi: 10.1038/ng1196-316.
A major transport function of the human intestine involves the absorption of chloride in exchange for bicarbonate. We have studied a recessively inherited defect of this exchange, congenital chloride diarrhoea (CLD; MIM 214700). The clinical presentation of CLD is a lifetime, potentially fatal diarrhoea with a high chloride content. The CLD locus was previously mapped to 7q3 adjacent to the cystic fibrosis gene (CFTR). By refined genetic and physical mapping, a cloned gene having anion transport function, Down-regulated in adenoma (DRA), was implicated as a positional and functional candidate for CLD. In this study, we report segregation of two missense mutations, delta V317 and H124L, and one frameshift mutation, 344delT, of DRA in 32 Finnish and four Polish CLD patients. The disease-causing nature of delta V317 is supported by genetic data in relation to the population history of Finland. By mRNA in situ hybridization, we demonstrate that the expression of DRA occurs preferentially in highly differentiated colonic epithelial cells, is unchanged in Finnish CLD patients with delta V317, and is low in undifferentiated (including neoplastic) cells. We conclude that DRA is an intestinal anion transport molecule that causes chloride diarrhoea when mutated.
人类肠道的一项主要转运功能涉及氯离子与碳酸氢根离子的交换吸收。我们研究了这种交换过程中一种隐性遗传缺陷，即先天性氯腹泻（CLD；MIM 214700）。CLD的临床表现为终生性、可能致命的高氯性腹泻。CLD基因位点先前被定位到7号染色体长臂3区，紧邻囊性纤维化基因（CFTR）。通过精细的遗传和物理图谱分析，一个具有阴离子转运功能的克隆基因——腺瘤下调基因（DRA），被认为是CLD的一个位置和功能候选基因。在本研究中，我们报告了在32名芬兰和4名波兰CLD患者中，DRA基因存在两种错义突变（V317缺失和H124L）以及一种移码突变（344delT）。与芬兰人群历史相关的遗传数据支持了V317缺失的致病性质。通过mRNA原位杂交，我们证明DRA的表达优先发生在高度分化的结肠上皮细胞中，在携带V317缺失的芬兰CLD患者中表达不变，而在未分化（包括肿瘤性）细胞中表达较低。我们得出结论，DRA是一种肠道阴离子转运分子，突变时会导致氯腹泻。
