Paw B H, Tieu P T, Kaback M M, Lim J, Neufeld E F
Department of Biological Chemistry, School of Medicine, University of California, Los Angeles 90024-1737.
Am J Hum Genet. 1990 Oct;47(4):698-705.
Mutations in the HEX A gene, encoding the alpha-subunit of beta-hexosaminidase A (Hex A), are the cause of Tay-Sachs disease as well as of juvenile, chronic, and adult GM2 gangliosidoses. We have examined the distribution of three mutations--a 4-nucleotide insertion in exon 11, a G----C transversion at a 5' splice site in intron 12, and a 269Gly----Ser amino acid substitution in exon 7--among individuals enzymatically diagnosed as carriers of Hex A deficiency. Mutation analysis included polymerase chain reaction (PCR) amplification of the relevant regions of genomic DNA, followed by allele-specific oligonucleotide hybridization; another test for heterozygosity of the exon 11 insertion was based on the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11, intron 12, exon 7, and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of Hex A deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation, the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe, whereas for the non-Jewish carriers it was western Europe. Because a twelfth of the Jewish carriers and four-fifths of the non-Jewish carriers of Hex A deficiency had mutant alleles other than the three common ones tested, enzyme-based tests cannot be replaced by DNA-based tests at the present time. However, DNA-based tests for two-carrier couples could identify those at risk for the chronic/adult GM2 gangliosidoses rather than for infantile Tay-Sachs disease.
编码β-己糖胺酶A（Hex A）α亚基的HEX A基因突变是导致泰-萨克斯病以及青少年型、慢性型和成人型GM2神经节苷脂贮积症的原因。我们检测了三种突变在经酶学诊断为Hex A缺乏症携带者的个体中的分布情况，这三种突变分别是：外显子11中的4个核苷酸插入、内含子12中5'剪接位点的G→C颠换以及外显子7中的269Gly→Ser氨基酸替换。突变分析包括对基因组DNA相关区域进行聚合酶链反应（PCR）扩增，随后进行等位基因特异性寡核苷酸杂交；另一种针对外显子11插入杂合性的检测基于低电泳迁移率异源双链PCR片段的形成。在156名犹太Hex A缺乏症携带者中，外显子11、内含子12、外显子7和未鉴定突变等位基因的百分比分布为73:15:4:8，在51名非犹太携带者中为16:0:3:81。无论突变情况如何，犹太携带者的祖先主要来自东欧和（频率稍低的）中欧，而非犹太携带者的祖先则来自西欧。由于Hex A缺乏症的犹太携带者中有十二分之一、非犹太携带者中有五分之四具有除所检测的三种常见突变之外的突变等位基因，目前基于酶的检测尚不能被基于DNA的检测所取代。然而，针对双携带者夫妇的基于DNA的检测可以识别出有患慢性/成人型GM2神经节苷脂贮积症风险的人，而非婴儿型泰-萨克斯病患者。
