Shore S, Tomczak J, Grebner E E, Myerowitz R
Laboratory of Biochemistry and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Hum Mutat. 1992;1(6):486-90. doi: 10.1002/humu.1380010606.
The Ashkenazi Jewish population is enriched for carriers of a fatal form of Tay-Sachs disease, a recessive inherited disorder caused by mutations in the alpha-chain of the lysosomal enzyme beta-hexosaminidase A. Approximately 20% of the Ashkenazi carriers harbor a splice junction defect while about 78% bear a 4 base pair (bp) insertion. However, the Ashkenazi Jewish patient used in the original description of the 4 bp insertion carried this lesion in only 1 allele and was negative for the splice junction mutation. We cloned the insertion negative allele and by sequence analysis of the exons found a point mutation in exon 11 that results in substitution of Trp392 with a premature termination codon. Nine Ashkenazi Jewish carriers that tested negative for the major and minor mutations as well as for a lesion causing an adult form of Tay-Sachs disease did not carry the base change defect, suggesting that it may be a recent and/or rare mutation. This finding also indicates that screening the Ashkenazi population solely by recombinant DNA methods for the splice junction, 4 bp insertion, and adult mutations may result in occasional false negatives.
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-萨克斯病是一种隐性遗传疾病，由溶酶体酶β-己糖胺酶A的α链突变引起。大约20%的阿什肯纳兹携带者存在剪接连接缺陷，约78%携带4个碱基对（bp）的插入。然而，在最初描述4 bp插入时所使用的阿什肯纳兹犹太患者仅一个等位基因携带此病变，且剪接连接突变呈阴性。我们克隆了插入阴性等位基因，并通过对外显子的序列分析在第11外显子中发现一个点突变，该突变导致色氨酸392被一个提前终止密码子取代。九名阿什肯纳兹犹太携带者对主要和次要突变以及导致成人形式泰-萨克斯病的病变检测均为阴性，他们并未携带碱基改变缺陷，这表明该突变可能是近期出现的和/或罕见的。这一发现还表明，仅通过重组DNA方法对阿什肯纳兹人群进行剪接连接、4 bp插入和成人突变的筛查可能偶尔会出现假阴性结果。
