本文選題：Gitelman綜合征　切入點(diǎn)：低鉀血癥　出處：《山東大學(xué)》2015年碩士論文

【摘要】：研究背景：低鉀血癥是臨床上常見的電解質(zhì)紊亂之一,在住院病人的發(fā)病率達(dá)20%。長期嚴(yán)重的鉀缺乏可導(dǎo)致葡萄糖耐量受損,嚴(yán)重的心、腎、神經(jīng)功能受損,甚至死亡。但是早期發(fā)現(xiàn)可以有效的糾正低鉀血癥,因此,及時(shí)準(zhǔn)確的識(shí)別低鉀血癥的病因?qū)τ谥委熓且豁?xiàng)極大的挑戰(zhàn)。Gitelman綜合征(Gitelman Syndrome, GS, OMIM 263800)是一種常見的遺傳型低鉀血癥的病因之一,發(fā)病率達(dá)25/1000000。其臨床特點(diǎn)主要表現(xiàn)為低鉀性堿中毒,低鎂血癥,低尿鈣,但是不伴有高血壓。該疾病是一種常染色體顯性遺傳病,是由于SLC12A3基因(GeneID:6559; MIM:600968; GeneBank: NC_000016.10)突變導(dǎo)致的,后者編碼遠(yuǎn)曲小管上的噻嗪類敏感鈉氯共轉(zhuǎn)運(yùn)體(thiazide-sensitive, electroneutral Na+-Cl_ cotransporter, NCC)。NCC蛋白是一段包含1000多個(gè)氨基酸的多肽,推測其二維結(jié)構(gòu)包含12個(gè)跨膜結(jié)構(gòu)域及胞內(nèi)親水的羧基端和氨基端,其中氨基端較短,羧基端較長。該疾病是一種高度異質(zhì)性的疾病,由于缺乏SLC12A3基因突變類型及臨床嚴(yán)重程度的相關(guān)關(guān)系的分析,因此,識(shí)別新的突變及基因型與表型相關(guān)關(guān)系分析有助于為NCC蛋白的功能學(xué)研究提供新的視角,并提高該疾病的轉(zhuǎn)歸率。對于基因突變的進(jìn)一步分析研究無疑對理解表型多樣性的機(jī)制提供幫助。研究目的：本研究主要調(diào)查兩個(gè)中國Gitelman綜合征家系的臨床及遺傳學(xué)特點(diǎn),并總結(jié)Gitelman綜合征在遺傳、診斷及治療方面的研究進(jìn)展。研究方法：選取兩個(gè)Gitelman綜合征非近親結(jié)婚三代家系,進(jìn)行SLC12A3基因突變篩查。對基因型及表型之間的關(guān)系進(jìn)行分析。研究結(jié)果：兩個(gè)先證者(先證者A及先證者B)的臨床特點(diǎn)為：低鉀血癥、低鎂血癥、低尿鈣,同時(shí)都不伴有高血壓。SLC12A3基因測序結(jié)果顯示兩個(gè)先證者均為復(fù)合雜合突變,且未被國內(nèi)外的研究多報(bào)道過,分別為：c.179CT和c.234delG; c.486-490delTACGGinsA和c.1925GA,推測這些突變可以導(dǎo)致蛋白結(jié)構(gòu)的破壞。家系中攜帶相同突變的女性攜帶者均比男性攜帶者癥狀輕。而且,先證者B的臨床癥狀較先證者A更輕,推測與其血鎂水平有關(guān)。在臨床隨訪的1年時(shí)間內(nèi),兩個(gè)先證者經(jīng)過補(bǔ)鉀、補(bǔ)鎂治療均取得滿意療效。研究結(jié)論：我們的研究顯示新發(fā)現(xiàn)的這兩個(gè)位于SLC12A3基因上的突變是導(dǎo)致Gitelman綜合征發(fā)生的病因,這為進(jìn)一步研究該基因的功能提供了更加深遠(yuǎn)的意義,同時(shí)也能使臨床工作人員更好的了解該疾病。
[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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R591.1

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