Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group.
Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group.
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一些患有泰萨克斯病的德系犹太人的剪接点突变：反对该族群内单一缺陷的证据。
DOI：
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发表时间：
1988
影响因子：
11.1
通讯作者：
R. Myerowitz
中科院分区：
文献类型：
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作者：
R. Myerowitz
泰-萨二氏病是一种遗传性疾病，其中溶酶体酶β-N-乙酰氨基己糖苷酶A的α链具有突变。德系犹太人被发现是一种严重的泰-萨克斯病的携带者，这种病是典型的泰-萨克斯病，发病率是普通人群的10倍。患有典型泰-萨二氏病的德系犹太人在临床和生化方面似乎是相同的，通常的假设是他们携带相同的α链突变。在这项研究中，我已经从一个德系犹太人的病人，GM 2968，与经典的泰-萨克斯病的α-链基因，并比较其核苷酸序列与正常的α-链基因的启动子区，外显子和剪接区，和多聚腺苷酸化信号区。在这些序列之间仅观察到一个差异：在内含子12的5'边界处，保守的剪接点二核苷酸序列G-T中的鸟苷被改变为胞苷。这种改变被认为是功能上显著的，并导致异常的mRNA剪接。利用聚合酶链反应扩增包含突变的区域，我开发了一种检测方法来筛选这种突变的患者和杂合子携带者。令人惊讶的是，在两名德系犹太人患者中，只有一个α链等位基因携带剪接点突变。这些患者中只有一位父母对缺陷呈阳性。另一名德系犹太人患者根本没有携带这种突变，受试者的父母也没有。此外，30%的专性杂合子进行测试的剪接点突变，而20德系犹太人指定的非运营商的酶法检测为阴性。这些数据与德系犹太人群体中典型的泰-萨克斯病的一种以上突变的存在是一致的。
Tay-Sachs disease is an inherited disorder in which the alpha chain of the lysosomal enzyme beta-N-acetylhexosaminidase A bears the mutation. Ashkenazi Jews are found to be carriers for a severe type of Tay-Sachs disease, the classic form, 10 times more frequently than the general population. Ashkenazi Jewish patients with classic Tay-Sachs disease have appeared to be clinically and biochemically identical, and the usual assumption has been that they harbor the same alpha-chain mutation. In this study I have isolated the alpha-chain gene from an Ashkenazi Jewish patient, GM2968, with classic Tay-Sachs disease and compared its nucleotide sequences with that of the normal alpha-chain gene in the promoter region, exon and splice junction regions, and polyadenylylation signal area. Only one difference was observed between these sequences: at the 5' boundary of intron 12, a guanosine in the conserved splice junction dinucleotide sequence G-T had been altered to a cytidine. The alteration is presumed to be functionally significant and to result in aberrant mRNA splicing. Utilizing the polymerase chain reaction to amplify the region encompassing the mutation, I developed an assay to screen patients and heterozygote carriers for this mutation. Surprisingly, in each of two Ashkenazi patients, only one alpha-chain allele harbored the splice junction mutation. Only one parent of each of these patients was positive for the defect. Another Ashkenazi patient did not bear this mutation at all nor did either of the subject's parents. In addition, 30% of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. The data are consistent with the presence of more than one mutation underlying the classic form of Tay-Sachs disease in the Ashkenazi Jewish population.