本文關(guān)鍵詞： Danon綜合征 LAMP2 DMD/BMD STR HA HMO EXT1 EXT2　出處：《浙江大學(xué)》2012年碩士論文　論文類型：學(xué)位論文

【摘要】：第一部分的研究工作中,我們收集了兩個患有Danon綜合征的中國人家系,進(jìn)行了分子遺傳學(xué)分析。 Danon綜合征(OMIM#300257)是一種罕見的X連鎖顯性遺傳病,該病的早發(fā)癥狀和體征主要包括心肌肥厚,骨骼肌病和智力發(fā)育遲緩。致病基因LAMP2(lysosome-associated membrane protein-2, LAMP2)位于Xq24,由9個外顯子組成,第9外顯子有不同剪切產(chǎn)生2種異構(gòu)體。LAMP2基因全長43218bp,編碼含410個氨基酸的溶酶體相關(guān)膜蛋白2(LAMP2)[GeneCards: http://www.genecards.org/cgi-bin/carddisp.pl?gene=LAMP2],是一種高度糖基化的溶酶體膜蛋白,參與維持溶酶體膜的完整性以及作為一種轉(zhuǎn)運(yùn)受體協(xié)助蛋白進(jìn)入溶酶體。本病的病理特點(diǎn)是在骨骼肌和心肌細(xì)胞內(nèi)存在含有自噬物質(zhì)和糖原的胞漿內(nèi)空泡。Danon綜合征的主要臨床特征男性患者和女性患者存在明顯的不同。男性患者通常表現(xiàn)典型的癥狀,心肌肥厚,骨骼肌病和智力發(fā)育遲緩,常在20歲前發(fā)病,大多數(shù)在30歲之前死亡。女性患者發(fā)病時間比男性晚,臨床癥狀和表現(xiàn)比男性患者輕,她們的癥狀通常只涉及心肌。 自Nishino首次發(fā)現(xiàn)LAMP2基因的8個突變,目前已有40多種不同突變在文獻(xiàn)中報道。本研究中,在兩個中國家庭的兩位男性患者中檢測到兩個LAMP2基因的新突變(c.808dupG和c.317-320dupCATC),二者都造成移碼突變,引起Danon綜合征。新突變的檢出豐富了Danon綜合征數(shù)據(jù)庫的信息。 第二部分的研究,是利用微衛(wèi)星多態(tài)標(biāo)志(STR)對6個遺傳病家系進(jìn)行了連鎖分析,其中包括4個杜氏(貝氏)進(jìn)行性肌營養(yǎng)不良癥(Duchenne Muscular Dystrophy/Baker Muscular Dystrophy, DMD/BMD)家系、1個血友病A(Hemophilia A, HA)家系和一個遺傳性多發(fā)性骨軟骨瘤(Hereditary Multiple Osteochondromas, HMO)家系。微衛(wèi)星多態(tài)標(biāo)志(Microsatellite, MS)又稱短串聯(lián)重復(fù)序列(Short tandem repeats, STR),是一種廣泛存在于人類基因組,以2-6個堿基為單位、串聯(lián)重復(fù)排列的序列。一般每個微衛(wèi)星位點(diǎn)有十幾個等位片段,具有高度的多態(tài)性,并符合孟德爾共顯性遺傳的特點(diǎn),具有高雜合度和多態(tài)信息量,可以作為一種遺傳標(biāo)記用于遺傳性疾病的診斷。采用PCR和STR連鎖分析法可以判斷遺傳病基因的走向,對遺傳性疾病基因診斷和產(chǎn)前診斷有重要意義。 本研究中,我們采用微衛(wèi)星標(biāo)記對DMD/BMD家系、HA家系和HMO家系進(jìn)行連鎖分析,探討STR在致病基因連鎖分析和產(chǎn)前診斷應(yīng)用中的意義以及局限性。
[Abstract]:In the first part, we collected two Chinese families with Danon syndrome for molecular genetic analysis. Danon syndrome (OMIM #300257) is a rare X-linked dominant hereditary disease. Its early onset symptoms and signs mainly include myocardial hypertrophy, skeletal myopathy and mental retardation. The pathogenic gene LAMP2(lysosome-associated membrane protein-2 (LAMP2) is located in Xq24 and consists of nine exons. Exon 9 has two isoforms produced by different splicing. LAMP2 gene is 43218bp in length and encodes lysosomal associated membrane protein 2GLAMP2 containing 410 amino acids. [gene Cardshttpwt / / www.genecards.orgcgi-bincarddisp.pl.] [GeneCards. / / www.genecards.orgcgi-bincard.pl. Gene=LAMP2 is a highly glycosylated lysosomal membrane protein. It is involved in maintaining the integrity of lysosomal membrane and entering lysosome as a transporter receptor assisting protein. The pathological features of the disease are the presence of cytosolic vacuoles containing autophagy and glycogen in skeletal muscle and cardiomyocytes. The main clinical features of the symptoms are significant differences between male and female patients. Male patients usually exhibit typical symptoms, Myocardial hypertrophy, skeletal myopathy and mental retardation often occur before the age of 20, and most of them die before the age of 30. The onset time of female patients is later than that of men, and their clinical symptoms and manifestations are lighter than that of male patients. Their symptoms usually involve only the myocardium. Eight mutations of LAMP2 gene have been first discovered by Nishino, and more than 40 different mutations have been reported in the literature. Two new mutations of LAMP2 gene, c.808dupG and c.317-320dupCATCG, were detected in two male patients from two Chinese families, both of which caused the Danon syndrome. The detection of the new mutation enriched the information of Danon syndrome database. In the second part, the linkage analysis of 6 families with hereditary diseases was carried out by using microsatellite polymorphism marker (STR). These include four Duchenne Muscular Dystrophy/Baker Muscular dystrophyts, one hemophilia Hemophilia A, and one hereditary multiple Multiple Osteochondromas. microsatellite polymorphism marker MSM. Short tandem repeats, short tandem repeats, are widely found in the human genome. Sequences arranged in tandem repetition in units of 2-6 bases. In general, each microsatellite locus has more than a dozen alleles, highly polymorphic, consistent with the characteristics of Mendelian codominant inheritance, with high heterozygosity and polymorphic information. It can be used as a genetic marker for the diagnosis of genetic diseases. PCR and STR linkage analysis can be used to determine the trend of genetic disease genes, which is of great significance for genetic diagnosis and prenatal diagnosis of hereditary diseases. In this study, we used microsatellite markers to analyze the linkage between HA and HMO families of DMD/BMD families, and to explore the significance and limitation of STR in the linkage analysis of pathogenic genes and prenatal diagnosis.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2012
【分類號】：R394.1

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相關(guān)期刊論文 前1條

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本文編號：1510749