Holtzman E J, Kolakowski L F, O'Brien D, Crawford J D, Ausiello D A
Renal Unit, (Medical Services), Massachusetts General Hospital, Charlestown 02129.
Hum Mol Genet. 1993 Aug;2(8):1201-4. doi: 10.1093/hmg/2.8.1201.
Congenital nephrogenic diabetes insipidus (DIR) is a rare X-linked hereditary disorder in which the renal collecting duct is unresponsive to arginine vasopressin; thus, the urine is consistently hypotonic to plasma. Recently, the association between the V2 receptor gene (AVPR2) and DIR has been proven. We have determined the gene sequence of four family members, from three generations, of a large North American family with CNDI who were originally part of the study used to formulate the Hopewell hypothesis. It had been proposed that a single DIR gene defect was introduced to North America by a member of an Ulster Scot kindred arriving on the ship Hopewell in 1761. DNA sequencing of the AVPR2 has identified a single base transversion from G-->A which changes tryptophan 71 to a stop codon in affected patients. This point mutation causes a truncation of the receptor leading to an essentially null allele. These data and other recently described mutations in the AVPR2 in North American pedigrees, descended from Ulster Scot ancestors and other origins, make the assertion of a founder effect proposed in the Hopewell hypothesis invalid.
先天性肾性尿崩症（DIR）是一种罕见的X连锁遗传性疾病，其中肾集合管对精氨酸加压素无反应；因此，尿液的渗透压始终低于血浆。最近，已证实V2受体基因（AVPR2）与DIR之间存在关联。我们测定了一个患有CNDI的北美大家庭中三代四名家庭成员的基因序列，该家庭最初是用于提出霍普韦尔假说的研究的一部分。有人提出，1761年乘坐“霍普韦尔号”船抵达的阿尔斯特苏格兰家族的一名成员将单一的DIR基因缺陷引入了北美。对AVPR2的DNA测序已确定在受影响的患者中存在一个从G到A的单碱基颠换，该颠换将色氨酸71变为一个终止密码子。这种点突变导致受体截短，产生一个基本无效的等位基因。这些数据以及最近在源自阿尔斯特苏格兰祖先和其他起源的北美家系中描述的AVPR2中的其他突变，使得霍普韦尔假说中提出的奠基者效应的断言无效。
