中国Gitelman综合征患者的基因型、表型分析及随访研究
发布时间：2019-01-27 19:42
【摘要】：研究目的:Gitelman综合征(GS)是由于SLCl2A3基因突变导致的遗传性肾小管疾病。本研究旨在对最大样本的中国Gitelman综合征患者进行基因型、表型分析和随访研究,并探讨Gitelman患者合并糖尿病的原因。研究方法:对67例Gitelman综合征患者进行SLC12A3基因突变分析。综合分析患者临床表现及生化特点,随访患者病情变化,并进行表型和基因型之间的相关性研究。行3h OGTT实验评价1例合并糖尿病的Gitelman综合征患者的胰岛素敏感性,对照组为健康受试者(n=10)和糖尿病患者(n=10)。研究结果:(1)67例GS患者SLCl2A3基因突变为41种,其中11个新突变,5(12.2%)个频发突变(p.T60M(28.4%),p.D486N(13.4%),p.R913Q(8.2%),c.965-1_c.977del GCGGACATTTTTGins ACCGAAAATTT(7.5%),c.2877_2878del AG(5.2%)),其中p.T60M是最常见的突变。3个家系(5.7%)是三倍体家系。(2)67例患者中,6例(9%)患者未发现典型的低尿钙症(24小时尿钙/尿肌酐0.1mmol/mmol),8例(11.9%)患者无明显的低镁血症(血镁0.65mmol/L)。另外,男性患者较女性患者出现更高的尿电解质排泄率和更早的发病年龄。(3)2名患者患有慢性肾脏病(e GFR60 m L/min?1.73m2),13名(19.4%)患者患有2型糖尿病,14名(20.9%)患者糖耐量减低(IGT),5名(7.5%)患者空腹血糖受损(IFG)。(4)2个等位基因上均有严重突变的患者(严重型基因组)比其他患者(轻微型基因组)有更高的FEK(p0.01),FEMg(p=0.038)和FECl(p=0.01)和临界意义上下降的血钾(p=0.07)水平;同时严重型基因组拥有更高比例的表型严重的患者。(5)OGTT实验结果提示合并糖尿病的Gitelman综合征患者未规律补充钾和镁时存在糖代谢和胰岛素功能异常,与健康受试者相比,GS患者表现为血糖和胰岛素分泌高峰延迟,血糖曲线下面积增加,胰岛素曲线下面积明显减少;胰岛素敏感性指标HOMA-IR升高,QUICKI和ISI降低;而通过规律补充电解质使得血糖恢复正常且最终停用降糖药物的GS患者和健康受试者的血糖和胰岛素曲线下面积、胰岛素敏感指标(HOMA-IR,QUICKI和ISI)水平趋势相似。研究结论:我们共确定41个与中国人群GS有关的SLC12A3突变位点,其中11个新突变和5个频发突变。本研究提示尿电解质排泄分数在GS患者表型评估中可能更为敏感。GS患者低血钾和低血镁难以纠正至正常。GS患者较普通人群具有更高的糖尿病患病风险。低钾血症和低镁血症可能是GS患者合并糖尿病的主要原因。
[Abstract]:Objective: Gitelman syndrome (GS) is an inherited renal tubular disease caused by SLCl2A3 gene mutation. The aim of this study was to investigate the genotype phenotypic analysis and follow-up study of the largest sample of Chinese patients with Gitelman syndrome and to explore the causes of diabetes in Gitelman patients. Methods: SLC12A3 gene mutation was analyzed in 67 patients with Gitelman syndrome. The clinical manifestations and biochemical characteristics of the patients were analyzed, and the relationship between phenotypes and genotypes were studied. Insulin sensitivity was evaluated in 1 patient with Gitelman syndrome with diabetes mellitus by 3 h OGTT test. The control group consisted of healthy subjects (n = 10) and diabetic patients (n = 10). Results: (1) there were 41 mutations in SLCl2A3 gene in 67 patients with GS. Among them, 11 new mutations, 5 (12.2%) frequent mutations (p.T60M (28.4%), p.D486N (13.4%), p.R913Q (8.2%). C.965-1_c.977del GCGGACATTTTTGins ACCGAAAATTT (7.5%, c.2877_2878del AG (5.2%), p.T60M was the most common mutation, 3 families (5.7%) were triploid families, (2) 67 patients, No typical hypocalcemia (24 hours urine calcium / creatinine 0.1mmol/mmol) was found in 6 patients (9%) and no significant hypomagnesemia (0.65mmol/L) was found in 8 patients (11.9%). In addition, men had higher urinary electrolyte excretion rate and earlier onset age than women. (3) two patients had chronic kidney disease (e GFR60 m L/min?1.73m2). 13 (19.4%) patients with type 2 diabetes and 14 (20.9%) patients with impaired glucose tolerance (IGT),) Five (7.5%) patients with impaired fasting blood glucose (IFG). (_ 4) had higher FEK (p0.01) in the two alleles (severe genome) than other patients (mild genome). The levels of FEMg (p0. 038) and FECl (p0. 01) and serum potassium (p0. 07) decreased in the critical sense. At the same time, there was a higher proportion of severe phenotypic patients in severe genomes. (5) the results of OGTT test showed that abnormal glucose metabolism and insulin function were found in patients with Gitelman syndrome complicated with diabetes mellitus during irregular potassium and magnesium supplementation, compared with those in healthy subjects. In GS patients, the peak of blood glucose and insulin secretion was delayed, the area under the blood glucose curve increased, and the area under the insulin curve decreased significantly. Insulin sensitivity index (HOMA-IR) was increased and QUICKI and ISI were decreased. However, the area under the curve of blood glucose and insulin, insulin sensitive index (HOMA-IR,QUICKI and ISI) of GS patients and healthy subjects whose blood glucose was restored to normal by regular electrolyte supplementation and the final stop of hypoglycemic drugs were similar in the trend of blood glucose and insulin sensitivity index (HOMA-IR,QUICKI and ISI). Conclusion: we identified 41 SLC12A3 mutation sites associated with GS in Chinese population, including 11 new mutations and 5 frequent mutations. This study suggests that urinary electrolyte excretion fraction may be more sensitive to phenotypic evaluation in patients with GS, hypokalemia and hypomagnesemia in patients with GS are difficult to correct to normal. Patients with GS have a higher risk of diabetes than the general population. Hypokalemia and hypomagnesemia may be the main causes of diabetes in GS patients.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R692;R587.1
本文编号：2416627
[Abstract]:Objective: Gitelman syndrome (GS) is an inherited renal tubular disease caused by SLCl2A3 gene mutation. The aim of this study was to investigate the genotype phenotypic analysis and follow-up study of the largest sample of Chinese patients with Gitelman syndrome and to explore the causes of diabetes in Gitelman patients. Methods: SLC12A3 gene mutation was analyzed in 67 patients with Gitelman syndrome. The clinical manifestations and biochemical characteristics of the patients were analyzed, and the relationship between phenotypes and genotypes were studied. Insulin sensitivity was evaluated in 1 patient with Gitelman syndrome with diabetes mellitus by 3 h OGTT test. The control group consisted of healthy subjects (n = 10) and diabetic patients (n = 10). Results: (1) there were 41 mutations in SLCl2A3 gene in 67 patients with GS. Among them, 11 new mutations, 5 (12.2%) frequent mutations (p.T60M (28.4%), p.D486N (13.4%), p.R913Q (8.2%). C.965-1_c.977del GCGGACATTTTTGins ACCGAAAATTT (7.5%, c.2877_2878del AG (5.2%), p.T60M was the most common mutation, 3 families (5.7%) were triploid families, (2) 67 patients, No typical hypocalcemia (24 hours urine calcium / creatinine 0.1mmol/mmol) was found in 6 patients (9%) and no significant hypomagnesemia (0.65mmol/L) was found in 8 patients (11.9%). In addition, men had higher urinary electrolyte excretion rate and earlier onset age than women. (3) two patients had chronic kidney disease (e GFR60 m L/min?1.73m2). 13 (19.4%) patients with type 2 diabetes and 14 (20.9%) patients with impaired glucose tolerance (IGT),) Five (7.5%) patients with impaired fasting blood glucose (IFG). (_ 4) had higher FEK (p0.01) in the two alleles (severe genome) than other patients (mild genome). The levels of FEMg (p0. 038) and FECl (p0. 01) and serum potassium (p0. 07) decreased in the critical sense. At the same time, there was a higher proportion of severe phenotypic patients in severe genomes. (5) the results of OGTT test showed that abnormal glucose metabolism and insulin function were found in patients with Gitelman syndrome complicated with diabetes mellitus during irregular potassium and magnesium supplementation, compared with those in healthy subjects. In GS patients, the peak of blood glucose and insulin secretion was delayed, the area under the blood glucose curve increased, and the area under the insulin curve decreased significantly. Insulin sensitivity index (HOMA-IR) was increased and QUICKI and ISI were decreased. However, the area under the curve of blood glucose and insulin, insulin sensitive index (HOMA-IR,QUICKI and ISI) of GS patients and healthy subjects whose blood glucose was restored to normal by regular electrolyte supplementation and the final stop of hypoglycemic drugs were similar in the trend of blood glucose and insulin sensitivity index (HOMA-IR,QUICKI and ISI). Conclusion: we identified 41 SLC12A3 mutation sites associated with GS in Chinese population, including 11 new mutations and 5 frequent mutations. This study suggests that urinary electrolyte excretion fraction may be more sensitive to phenotypic evaluation in patients with GS, hypokalemia and hypomagnesemia in patients with GS are difficult to correct to normal. Patients with GS have a higher risk of diabetes than the general population. Hypokalemia and hypomagnesemia may be the main causes of diabetes in GS patients.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R692;R587.1
【参考文献】
相关期刊论文 前2条
1 王艳;韩正斌;邵乐平;栾健;刘军;;10例Gitelman综合征患者SLC12A3基因的检测[J];肾脏病与透析肾移植杂志;2015年05期
2 董晖;郎艳华;邵泽平;李林;邵乐平;;Gitelman综合征合并甲状腺疾病:两例患者SLC12A3基因分析[J];中华内分泌代谢杂志;2010年05期
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