A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies
A new mutation (intron 9+1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies
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DOI：
10.1111/j.1523-1755.2004.00388.x
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发表时间：
2004-01-01
影响因子：
19.6
通讯作者：
Santos, F
中科院分区：
文献类型：
--
作者：
Coto, E;Rodriguez, J;Santos, F
背景Gitel综合征是一种遗传性肾小管疾病，其特征是肾源性代谢紊乱、低钾血症和低镁血症以及低钙尿。大多数Gitelman综合征患者携带SLC 12 A3基因失活突变，该基因编码位于远曲小管的钠-氯协同转运蛋白。本研究的目的是探讨潜在的突变Gitelman综合征患者的吉普赛人来自不同的地理来源。20例吉普赛Gitelman综合征患者的临床和生化特征进行了调查的突变分析。这些患者来自12个不相关的吉普赛家庭，生活在四个不同的欧洲国家。每个患者的父母和未受影响的兄弟姐妹，以及200名健康对照患者的DNA也进行了分析。所有患者均为SLC 12 A3基因第9内含子第1位鸟嘌呤突变为胸腺嘧啶的纯合子。在对照人群中未发现该突变。父母的突变是杂合子。尽管有一个共同的突变，但患者综合征的临床表现各不相同，从6名儿童无症状到4名儿童严重生长迟缓。在我们的Gitelman综合征吉普赛家族队列中，SLC 12 A3基因内一种新的点突变的证明高度提示了创始人效应。这一发现将有助于在吉普赛人中进一步确定Gitelman综合征病例的遗传缺陷。我们的研究代表了有史以来发表的最大系列的Gitelman综合征患者具有相同的潜在突变，并支持这种疾病的基因型和临床表型之间缺乏相关性。
Background. Gitel syndrome is an inherited tubular disorder characterized by metabolic alkalosis, hypokalemia, and hypomagnesemia of renal origin and hypocalciuria. The majority of patients with Gitelman syndrome carry inactivating mutations in the SLC12A3 gene encoding the sodium-chloride cotransporter located in the distal convoluted tubule. The purpose of this study was to investigate the underlying mutation in Gitelman syndrome patients of Gypsy race from different geographic origin.Methods. Twenty Gypsy patients with clinical and biochemical features of Gitelman syndrome were investigated by mutational analysis. The patients belonged to 12 unrelated Gypsy families living in four different European countries. The parents and unaffected siblings of each patient, as well as the DNA of a population of 200 healthy control patients, were also analyzed.Results. All patients were homozygous for the same splice site mutation, guanine to thymine in the first position of intron 9 of SLC12A3 gene. This mutation was not found in the control population. Parents were heterozygous for the mutation. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms in six children to severe growth retardation in four.Conclusion. Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.