Division of Pediatric Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, 33305 Taiwan.
J Clin Endocrinol Metab. 2012 Aug;97(8):E1478-82. doi: 10.1210/jc.2012-1707. Epub 2012 Jun 7.
Genotype, phenotype, and follow-up analysis is rarely performed in a large number of patients with Gitelman's syndrome (GS) caused by mutations in SLC12A3 encoding the thiazide-sensitive NaCl cotransporter.
DESIGN, SETTING, AND PATIENTS: One hundred seventeen Taiwanese GS patients (70 males and 47 females, age 24 ± 10 yr) with SLC12A3 mutations belonging to 92 unrelated families were investigated. Genomic DNA and/or cDNA from blood leukocytes were analyzed for SLC12A3 mutations and haplotype analysis with intragenic and extragenic markers for recurrent SLC12A3 mutations. Clinical symptoms and biochemical studies at the first presentation as well as follow-up were examined.
Forty different SLC12A3 mutations were identified. Approximately 12% of patients had triple SLC12A3 mutations. Fourteen mutations were recurrent with only one founder effect (S710X). Typical hypocalciuria and hypomagnesemia were not found in seven and nine patients, respectively. In addition to male patients having an earlier age of onset, more severe hypokalemia, and significantly lower serum aldosterone concentration, patients with homozygous and deep mutations in intron 13 (c.1670-191C → T) had more severe phenotype. Seven and five patients had chronic kidney disease (stage III-IV) and type 2 diabetes at the follow-up, respectively.
Screening of recurrent hot spot SLC12A3 mutations may provide an early diagnosis of GS. Besides gender effect, the nature of homozygous and deep intronic mutations may influence the phenotype. Patients with GS may be at increased risk for the development of chronic kidney disease and type 2 diabetes.
由于编码噻嗪类敏感的 NaCl 共转运蛋白的 SLC12A3 基因突变，导致的 Gitelman 综合征（GS）患者数量众多，但对其进行基因型、表型和随访分析的情况却很少见。
设计、地点和患者：对 92 个无关家族的 117 例台湾 GS 患者（70 名男性和 47 名女性，年龄 24±10 岁）进行了研究。对血液白细胞的基因组 DNA 和/或 cDNA 进行 SLC12A3 基因突变分析，并采用基因内和基因外标记物进行常见 SLC12A3 突变的单体型分析。对首次就诊时的临床症状和生化研究以及随访情况进行了检查。
发现了 40 种不同的 SLC12A3 突变。大约 12%的患者存在三重 SLC12A3 突变。14 种突变是常见的，只有一种起源效应（S710X）。7 名和 9 名患者分别没有典型的低钙尿和低镁血症。除了男性患者发病年龄更早、更严重的低钾血症和显著更低的血清醛固酮浓度外，13 号内含子（c.1670-191C→T）纯合和深突变的患者表型更严重。在随访时，7 名和 5 名患者分别患有慢性肾脏病（III-IV 期）和 2 型糖尿病。
筛查常见热点 SLC12A3 突变可能有助于早期诊断 GS。除性别影响外，纯合和深内含子突变的性质可能会影响表型。GS 患者发生慢性肾脏病和 2 型糖尿病的风险可能会增加。
