Mastroianni N, Bettinelli A, Bianchetti M, Colussi G, De Fusco M, Sereni F, Ballabio A, Casari G
Telethon Institute of Genetics and Medicine (Tigem), San Raffaele Biomedical Science Park, Milan.
Am J Hum Genet. 1996 Nov;59(5):1019-26.
A hereditary defect of the distal tubule accounts for the clinical features of Gitelman syndrome (GS), an autosomal recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Recently, we cloned the cDNA coding for the human Na-Cl thiazide-sensitive cotransporter (TSC; also known as ¿NCCT¿ or ¿SLC12A3¿) as a possible candidate for GS, and Simon et al., independently, described mutations in patients with GS. Now, we show 12 additional mutations consistent with a loss of function of the Na-Cl cotransporter in GS. Two missense replacements, R209W and P349L, are common to both studies and could represent ancient mutations. The other mutations include three deletions, two insertions, and six missense mutations. When all mutations from both studies are considered, missense mutations seem to be more frequently localized within the intracellular domains of the molecule, rather than in transmembrane or extracellular domains. One family, previously reported as a GS form with dominant inheritance, has proved to be recessive, with the affected child being a compound heterozygote. A highly informative intragenic tetranucleotide marker, useful for molecular diagnostic studies, has been identified at the acceptor splice site of exon 9.
远端肾小管的遗传性缺陷导致了吉特曼综合征（GS）的临床特征，这是一种常染色体隐性疾病，其特点为低钾血症、低镁血症、代谢性碱中毒和低钙尿症。最近，我们克隆了编码人钠 - 氯噻嗪敏感共转运体（TSC；也称为“NCCT”或“SLC12A3”）的cDNA，将其作为GS的一个可能候选基因，并且西蒙等人独立描述了GS患者中的突变。现在，我们展示了另外12个与GS中钠 - 氯共转运体功能丧失一致的突变。两项研究中均出现了两个错义替换，即R209W和P349L，它们可能代表古老的突变。其他突变包括三个缺失、两个插入和六个错义突变。当考虑两项研究中的所有突变时，错义突变似乎更频繁地定位在该分子的细胞内结构域，而非跨膜或细胞外结构域。一个先前报道为具有显性遗传的GS形式的家族，已被证明为隐性遗传，患病儿童为复合杂合子。在外显子9的受体剪接位点处鉴定出了一个对分子诊断研究非常有用的高信息含量基因内四核苷酸标记。
