中國Gitelman綜合征患者的基因型、表型分析及隨訪研究
發(fā)布時間：2019-01-27 19:42
【摘要】：研究目的:Gitelman綜合征(GS)是由于SLCl2A3基因突變導(dǎo)致的遺傳性腎小管疾病。本研究旨在對最大樣本的中國Gitelman綜合征患者進行基因型、表型分析和隨訪研究,并探討Gitelman患者合并糖尿病的原因。研究方法:對67例Gitelman綜合征患者進行SLC12A3基因突變分析。綜合分析患者臨床表現(xiàn)及生化特點,隨訪患者病情變化,并進行表型和基因型之間的相關(guān)性研究。行3h OGTT實驗評價1例合并糖尿病的Gitelman綜合征患者的胰島素敏感性,對照組為健康受試者(n=10)和糖尿病患者(n=10)。研究結(jié)果:(1)67例GS患者SLCl2A3基因突變?yōu)?1種,其中11個新突變,5(12.2%)個頻發(fā)突變(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是最常見的突變。3個家系(5.7%)是三倍體家系。(2)67例患者中,6例(9%)患者未發(fā)現(xiàn)典型的低尿鈣癥(24小時尿鈣/尿肌酐0.1mmol/mmol),8例(11.9%)患者無明顯的低鎂血癥(血鎂0.65mmol/L)。另外,男性患者較女性患者出現(xiàn)更高的尿電解質(zhì)排泄率和更早的發(fā)病年齡。(3)2名患者患有慢性腎臟病(e GFR60 m L/min?1.73m2),13名(19.4%)患者患有2型糖尿病,14名(20.9%)患者糖耐量減低(IGT),5名(7.5%)患者空腹血糖受損(IFG)。(4)2個等位基因上均有嚴(yán)重突變的患者(嚴(yán)重型基因組)比其他患者(輕微型基因組)有更高的FEK(p0.01),FEMg(p=0.038)和FECl(p=0.01)和臨界意義上下降的血鉀(p=0.07)水平;同時嚴(yán)重型基因組擁有更高比例的表型嚴(yán)重的患者。(5)OGTT實驗結(jié)果提示合并糖尿病的Gitelman綜合征患者未規(guī)律補充鉀和鎂時存在糖代謝和胰島素功能異常,與健康受試者相比,GS患者表現(xiàn)為血糖和胰島素分泌高峰延遲,血糖曲線下面積增加,胰島素曲線下面積明顯減少;胰島素敏感性指標(biāo)HOMA-IR升高,QUICKI和ISI降低;而通過規(guī)律補充電解質(zhì)使得血糖恢復(fù)正常且最終停用降糖藥物的GS患者和健康受試者的血糖和胰島素曲線下面積、胰島素敏感指標(biāo)(HOMA-IR,QUICKI和ISI)水平趨勢相似。研究結(jié)論:我們共確定41個與中國人群GS有關(guān)的SLC12A3突變位點,其中11個新突變和5個頻發(fā)突變。本研究提示尿電解質(zhì)排泄分數(shù)在GS患者表型評估中可能更為敏感。GS患者低血鉀和低血鎂難以糾正至正常。GS患者較普通人群具有更高的糖尿病患病風(fēng)險。低鉀血癥和低鎂血癥可能是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.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R692;R587.1
本文編號：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.
【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R692;R587.1
【參考文獻】
相關(guān)期刊論文 前2條
1 王艷;韓正斌;邵樂平;欒健;劉軍;;10例Gitelman綜合征患者SLC12A3基因的檢測[J];腎臟病與透析腎移植雜志;2015年05期
2 董暉;郎艷華;邵澤平;李林;邵樂平;;Gitelman綜合征合并甲狀腺疾病:兩例患者SLC12A3基因分析[J];中華內(nèi)分泌代謝雜志;2010年05期
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