Mules E H, Hayflick S, Miller C S, Reynolds L W, Thomas G H
Genetics Laboratory, Kennedy Institute, Baltimore, MD 21205.
Am J Hum Genet. 1992 Apr;50(4):834-41.
Initial investigations demonstrated that only 3/34 "Tay-Sachs chromosomes" in 22 unrelated, non-Jewish patients or carriers of some form of GM2-gangliosidosis (7 black and 15 non-Jewish Caucasian) had either of the two mutations commonly found in the Jewish population. To determine the nature and incidence of the alterations in this non-Jewish population we have utilized PCR, single-strand conformation polymorphism analysis and sequencing to detect new mutations in genomic DNA. Fourteen primer sets have been utilized to analyze 80% of the coding region and 23/26 splice sites of the gene coding for the alpha chain of hexosaminidase A. Presumed deleterious mutations were discovered in 17/34 chromosomes believed to be carrying a beta-hexosaminidase A alpha-subunit gene mutation. Ten had abnormalities which have been described previously. In the remaining 24 Tay-Sachs disease alleles, six novel mutations predicted to be deleterious were discovered. These include two small deletions (a single-base frameshift and a three-base deletion removing an amino acid), two different nonsense mutations, an initiation codon mutation (ATG----GTG), and a missense mutation (Arg499Cys) in a highly conserved residue. In addition, three presumed nondeleterious mutations were found.
初步调查表明，在22名无亲缘关系的非犹太患者或某种形式GM2神经节苷脂贮积症携带者（7名黑人及15名非犹太白种人）的34条“泰-萨克斯染色体”中，只有3条具有犹太人群中常见的两种突变中的任何一种。为了确定该非犹太人群中变异的性质和发生率，我们利用聚合酶链反应（PCR）、单链构象多态性分析和测序来检测基因组DNA中的新突变。已使用14组引物分析了编码己糖胺酶Aα链的基因的80%编码区和26个剪接位点中的23个。在被认为携带β-己糖胺酶Aα亚基基因突变的34条染色体中的17条上发现了推测有害的突变。其中10条具有先前已描述的异常。在其余24个泰-萨克斯病等位基因中，发现了6个预计有害的新突变。这些包括两个小缺失（一个单碱基移码和一个去除一个氨基酸的三碱基缺失）、两个不同的无义突变、一个起始密码子突变（ATG→GTG）以及一个高度保守残基中的错义突变（Arg499Cys）。此外，还发现了3个推测无害的突变。
