两Gitelman综合征家系分子致病机制研究

发布时间：2018-03-26 15:46

本文选题：Gitelman综合征　切入点：低钾血症　出处：《山东大学》2015年硕士论文

【摘要】：研究背景：低钾血症是临床上常见的电解质紊乱之一,在住院病人的发病率达20%。长期严重的钾缺乏可导致葡萄糖耐量受损,严重的心、肾、神经功能受损,甚至死亡。但是早期发现可以有效的纠正低钾血症,因此,及时准确的识别低钾血症的病因对于治疗是一项极大的挑战。Gitelman综合征(Gitelman Syndrome, GS, OMIM 263800)是一种常见的遗传型低钾血症的病因之一,发病率达25/1000000。其临床特点主要表现为低钾性碱中毒,低镁血症,低尿钙,但是不伴有高血压。该疾病是一种常染色体显性遗传病,是由于SLC12A3基因(GeneID:6559; MIM:600968; GeneBank: NC_000016.10)突变导致的,后者编码远曲小管上的噻嗪类敏感钠氯共转运体(thiazide-sensitive, electroneutral Na+-Cl_ cotransporter, NCC)。NCC蛋白是一段包含1000多个氨基酸的多肽,推测其二维结构包含12个跨膜结构域及胞内亲水的羧基端和氨基端,其中氨基端较短,羧基端较长。该疾病是一种高度异质性的疾病,由于缺乏SLC12A3基因突变类型及临床严重程度的相关关系的分析,因此,识别新的突变及基因型与表型相关关系分析有助于为NCC蛋白的功能学研究提供新的视角,并提高该疾病的转归率。对于基因突变的进一步分析研究无疑对理解表型多样性的机制提供帮助。研究目的：本研究主要调查两个中国Gitelman综合征家系的临床及遗传学特点,并总结Gitelman综合征在遗传、诊断及治疗方面的研究进展。研究方法：选取两个Gitelman综合征非近亲结婚三代家系,进行SLC12A3基因突变筛查。对基因型及表型之间的关系进行分析。研究结果：两个先证者(先证者A及先证者B)的临床特点为：低钾血症、低镁血症、低尿钙,同时都不伴有高血压。SLC12A3基因测序结果显示两个先证者均为复合杂合突变,且未被国内外的研究多报道过,分别为：c.179CT和c.234delG; c.486-490delTACGGinsA和c.1925GA,推测这些突变可以导致蛋白结构的破坏。家系中携带相同突变的女性携带者均比男性携带者症状轻。而且,先证者B的临床症状较先证者A更轻,推测与其血镁水平有关。在临床随访的1年时间内,两个先证者经过补钾、补镁治疗均取得满意疗效。研究结论：我们的研究显示新发现的这两个位于SLC12A3基因上的突变是导致Gitelman综合征发生的病因,这为进一步研究该基因的功能提供了更加深远的意义,同时也能使临床工作人员更好的了解该疾病。
[Abstract]:Background: hypokalemia is one of the most common electrolyte disorders in clinic, and the incidence rate in inpatients is 20. Long-term severe potassium deficiency can lead to impaired glucose tolerance, severe heart, kidney and nerve function. Even death. But early detection can effectively correct hypokalemia, so, Timely and accurate identification of the etiology of hypokalemia is a great challenge for treatment. Gitelman Syndrome, GS263800) is one of the common causes of hereditary hypokalemia, with an incidence of 25 / 1000000. Its clinical features are mainly hypokalemic alkalosis. Hypomagnesemia, hypocalcemia, but no hypertension. The disease is an autosomal dominant genetic disorder caused by mutations in the gene gene gene ID: 6559; MIM: 600368; gene bank: NCSTT 000016.10). The latter encodes thiazide-sensitive thiazide-sensitive, electroneutral Na Clcotransporter, NCC).NCC protein on distal convoluted tubules, a polypeptide containing more than 1000 amino acids. It is assumed that its two-dimensional structure consists of 12 transmembrane domains and carboxyl and amino ends of intracellular hydrophilic. The amino terminal is shorter, the carboxyl terminal is longer. The disease is a highly heterogeneous disease. Due to the lack of SLC12A3 gene mutation type and clinical severity of the correlation analysis, therefore, Identification of new mutations and phenotypic correlation analysis may provide a new perspective for the functional study of NCC protein. Further analysis of gene mutation will undoubtedly contribute to understanding the mechanism of phenotypic diversity. Objective: to investigate the clinical and genetic characteristics of two Chinese families with Gitelman syndrome. The research progress in inheritance, diagnosis and treatment of Gitelman syndrome was summarized. The relationship between genotype and phenotype was analyzed. Results: the clinical characteristics of two proband (proband A and B) were as follows: hypokalemia, hypomagnesemia, hypocalcemia, hypocalcemia, The results of sequencing showed that both of the two probands were heterozygous mutations, and had not been reported in domestic and foreign studies at home and abroad, at the same time, the gene sequencing of SLC12A3 gene without hypertension showed that the two probands were heterozygous. C.486-490delTACGGinsA and c.1925GA, respectively. These mutations may lead to the destruction of the protein structure. The female carriers with the same mutation in the pedigree have lighter symptoms than the male carriers. Moreover, the clinical symptoms of the proband B are lighter than those of the proband A. During the 1-year follow-up period, the two proband were treated with potassium supplementation. Conclusion: our study shows that the two mutations located in the SLC12A3 gene are the etiology of Gitelman syndrome, which provides a more profound significance for further study of the function of the gene. At the same time, it can also make the clinical staff better understand the disease.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R591.1

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