Myerowitz R, Costigan F C
Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
J Biol Chem. 1988 Dec 15;263(35):18587-9.
The Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay-Sachs disease, an inherited disorder caused by mutations in the alpha-chain of the lysosomal enzyme, beta-hexosaminidase A. Until recently it was presumed that Tay-Sachs patients from this ethnic isolate harbored the same alpha-chain mutation. This was disproved by identification of a splice junction defect in the alpha-chain of an Ashkenazi patient which could be found in only 20-30% of the Ashkenazi carriers tested. In this study we have isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM515, with classic Tay-Sachs disease who was negative for the splice junction defect. Sequence analysis of the promoter region, exon and splice junctions regions, and polyadenylation signal area revealed a 4-base pair insertion in exon 11. This mutation introduces a premature termination signal in exon 11 which results in a deficiency of mRNA in Ashkenazi patients. A dot blot assay was developed to screen patients and heterozygote carriers for the insertion mutation. The lesion was found in approximately 70% of the carriers tested, thereby distinguishing it as the major defect underlying Tay-Sachs disease in the Ashkenazi Jewish population.
阿什肯纳兹犹太人群中携带致命形式的泰-萨克斯病的携带者比例较高，泰-萨克斯病是一种由溶酶体酶β-己糖胺酶A的α链突变引起的遗传性疾病。直到最近，人们还认为来自这个族群隔离群体的泰-萨克斯病患者携带相同的α链突变。一名阿什肯纳兹患者的α链中发现了一个剪接连接缺陷，这一发现推翻了上述观点，因为在接受检测的阿什肯纳兹携带者中，只有20%-30%存在这种缺陷。在本研究中，我们从一名患有典型泰-萨克斯病的阿什肯纳兹犹太患者GM515中分离出α链基因，该患者的剪接连接缺陷检测呈阴性。对启动子区域、外显子和剪接连接区域以及聚腺苷酸化信号区域的序列分析显示，外显子11中有一个4碱基对的插入。这种突变在外显子11中引入了一个提前终止信号，导致阿什肯纳兹患者中mRNA缺乏。我们开发了一种斑点印迹分析法，用于筛查患者和杂合子携带者是否存在插入突变。在大约70%接受检测的携带者中发现了这种病变，因此将其确定为阿什肯纳兹犹太人群中泰-萨克斯病的主要缺陷。
