Akerman B R, Zielenski J, Triggs-Raine B L, Prence E M, Natowicz M R, Lim-Steele J S, Kaback M M, Mules E H, Thomas G H, Clarke J T
McGill University-Montreal Children's Hospital Research Institute, Quebec, Canada.
Hum Mutat. 1992;1(4):303-9. doi: 10.1002/humu.1380010407.
Tay-Sachs disease (TSD) is an autosomal recessive genetic disorder resulting from mutation of the HEXA gene encoding the alpha-subunit of the lysosomal enzyme, beta-N-acetylhexosaminidase A (Hex A). We have discovered that a Tay-Sachs mutation, IVS-9 + 1 G-->A, first detected by Akli et al. (Genomics 11:124-134, 1991), is a common disease allele in non-Jewish Caucasians (10/58 alleles examined). A PCR-based diagnostic test, which detects an NlaIII site generated by the mutation, revealed a frequency among enzyme-defined carriers of 9/64 (14%). Most of those carrying the allele trace their origins to the United Kingdom, Ireland, or Western Europe. It was not identified among 12 Black American TSD alleles or in any of 18 Ashkenazi Jewish, enzyme-defined carriers who did not carry any of the mutations common to this population. No normally spliced RNA was detected in PCR products generated from reverse transcription of RNA carrying the IVS-9 mutation. Instead, the low levels of mRNA from this allele were comprised of aberrant species resulting from the use of either of two cryptic donor sites, one truncating exon 9 and the other within IVS-9, spliced to exon 10. Numerous additional splice products were detected, most involving skipping of one or more surrounding exons. Together with a recently identified allele responsible for Hex A pseudodeficiency (Triggs-Raine et al. Am J Hum Genet, 1992), these two alleles accounted for almost 50% (29/64) of TSD or carrier alleles ascertained by enzyme screening tests in non-Jewish Caucasians.
泰-萨克斯病（TSD）是一种常染色体隐性遗传病，由编码溶酶体酶β-N-乙酰己糖胺酶A（Hex A）α亚基的HEXA基因突变引起。我们发现，Akli等人（《基因组学》11:124 - 134，1991年）首次检测到的泰-萨克斯突变IVS-9 + 1 G→A，是在非犹太白种人中常见的致病等位基因（检测的58个等位基因中有10个）。一种基于聚合酶链反应（PCR）的诊断测试，可检测由该突变产生的NlaIII位点，结果显示在酶学定义的携带者中该突变频率为9/64（14%）。大多数携带该等位基因的人祖籍是英国、爱尔兰或西欧。在12个美国黑人TSD等位基因中未发现该突变，在18个未携带该人群常见突变的阿什肯纳兹犹太酶学定义携带者中也未发现。在携带IVS-9突变的RNA逆转录产生的PCR产物中未检测到正常剪接的RNA。相反，该等位基因的低水平信使核糖核酸（mRNA）由异常种类组成，这些异常种类是由于使用了两个隐蔽供体位点之一产生的，一个使外显子9截短，另一个在IVS-9内，与外显子10拼接。还检测到许多其他剪接产物，大多数涉及一个或多个周围外显子的跳跃。与最近发现的导致Hex A假缺陷的一个等位基因（Triggs-Raine等人，《美国人类遗传学杂志》，1992年）一起，这两个等位基因在非犹太白种人中通过酶筛选测试确定的TSD或携带者等位基因中占近50%（29/64）。
