一个粘脂贮积症Ⅲ型家系的分子遗传学研究

发布时间：2018-05-05 20:22

  本文选题：粘脂贮积症 + 连锁分析　； 参考：《华中科技大学》2009年硕士论文

【摘要】：粘脂贮积症三型是一种溶酶体贮积病,是溶酶体酶N-乙酰基-1-磷酸转移酶(GlcNAc -phosphotransferase, GlcNAc-PT)活性缺失使得溶酶体酶不能正常进入溶酶体的常染色体隐性遗传病。GlcNAc-PT蛋白以复合体形式存在,其中α/β亚基由GNPTAB基因编码,γ亚基由GNPTAG基因编码。在这一研究中,我们收集了一个有四代人的中国人家系,其中有四人患有粘脂贮积症。连锁分析显示这个中国家系的致病基因和12号染色体上的Marker D20S346连锁。已报道的致病基因GNPTAB正座位于此位置。通过对GNPTAB的测序分析,在这一家系中发现了一个杂合的突变,一个为已报道的剪切突变IVS13+1GA(C.2715+GA),另一个为新发现的无义突变p.R364X(c.1090CT)。这个家系的四个病人都带有这两个突变。这个家系中的其他正常人与226个正常人对照中也未发现该突变的存在。根据以前的报道,剪切突变IVS13+1GA(c.2715+1GA)使得该基因转录时跳过13号外显子的1103bp碱基,导致剪接直接由12号外显子到14号外显子。新发现的无义突变p.R364X(c.1090CT)使得GNPTAB基因的α亚基编码的蛋白截短,从而产生了一个截短的α亚基编码蛋白而β亚基编码蛋白的完全丢失。这一研究是第一次在中国人群中报道的GNPTAB基因杂合型突变导致MLⅢ,并且拓宽了GNPTAB导致MLⅢ的突变谱。对这两个突变的进一步研究有助于我们更好的理解GNPTAB的基因功能,以及GNPTAB突变和MLⅢ疾病表型之间的关系。
[Abstract]:Mucolipidosis type III is a lysosomal storage disease. The absence of lysosomal enzyme GlcNAc -phosphotransferase (GlcNAc-PTT) makes lysosomal enzymes not normally enter the lysosomal autosomal recessive hereditary disease. GlcNAc-PT protein exists in the form of complex. The 伪 / 尾 subunit is encoded by GNPTAB gene, and 纬 subunit is encoded by GNPTAG gene. In this study, we collected a family of four generations of Chinese, four of whom suffered from mucoid storage. Linkage analysis showed that the pathogenicity gene of this strain was linked to the Marker D20S346 on chromosome 12. The reported pathogenicity gene GNPTAB is located at this location. By sequencing the GNPTAB, a heterozygous mutation was found in this pedigree, one was a reported shearing mutation IVS13 1GA(C.2715 GAA, and the other was a newly discovered nonsense mutation, p. R364XC1090CTA. All four patients in this family have these two mutations. The mutation was also not found in other healthy individuals in this family compared with 226 healthy controls. According to previous reports, IVS13 1GA(c.2715 1GA) caused the gene to skip the 1103bp base of exon 13 during transcription, leading to splicing directly from exon 12 to exon 14. The newly discovered pointless mutation p.R364XC1090CT) truncated the 伪 subunit of GNPTAB gene, resulting in a truncated 伪 subunit encoding protein and a complete loss of 尾 subunit coding protein. This study is the first reported heterozygous mutation of GNPTAB gene leading to ML 鈪，

本文编号：1849165