Yoshida K, Oshima A, Shimmoto M, Fukuhara Y, Sakuraba H, Yanagisawa N, Suzuki Y
Department of Clinical Genetics, Tokyo Metropolitan Institute of Medical Science, Japan.
Am J Hum Genet. 1991 Aug;49(2):435-42.
Molecular analysis of the human beta-galactosidase gene revealed six different mutations in 10 of 11 Japanese GM1-gangliosidosis patients. They were the only abnormalities in each allele examined in this study. A 165-nucleotide duplication (positions 1103-1267) was found in two infantile patients, producing an abnormally large mRNA; one patient was probably a homozygote, and the other was a heterozygote of this mutation. The other two infantile patients had different mutations; a 123 Gly(GGG)----Arg(AGG) mutation in one patient and a 316 Tyr(TAT)----Cys(TGT) mutation in the other. A 201 Arg(CGC)----Cys(TGC) mutation, eliminating a BspMI site, was detected in a late-infantile/juvenile patient; the restriction-site analysis of amplified genomic DNA confirmed his heterozygosity for this mutation. A 51 Ile(ATC)----Thr(ACC) mutation was found in all five adult/chronic patients examined in this study. It created a SauI site, and restriction-site analysis confirmed that four patients were homozygous mutants. The other was a compound heterozygote for this mutation and another 457 Arg(CGA)----Gln(CAA) mutation. These mutant genes expressed markedly decreased or completely deficient enzyme activities in beta-galactosidase-deficient human fibroblasts transformed by adenovirus-SV40 recombinants. We conclude that gene mutations are heterogeneous in GM1-gangliosidosis but that the 51 Ile(ATC)----Thr(ACC) mutation is common among the Japanese adult/chronic cases. Genotype-phenotype correlations in GM1-gangliosidosis are briefly discussed.
对人类β-半乳糖苷酶基因的分子分析显示，在11名日本GM1神经节苷脂贮积症患者中的10名患者身上发现了6种不同的突变。它们是本研究中所检测的每个等位基因中的唯一异常。在两名婴儿型患者中发现了一个165个核苷酸的重复序列（位置1103 - 1267），产生了异常大的mRNA；一名患者可能是该突变的纯合子，另一名是杂合子。另外两名婴儿型患者有不同的突变；一名患者发生了123位甘氨酸（GGG）突变为精氨酸（AGG）的突变，另一名患者发生了316位酪氨酸（TAT）突变为半胱氨酸（TGT）的突变。在一名晚婴/青少年型患者中检测到一个201位精氨酸（CGC）突变为半胱氨酸（TGC）的突变，该突变消除了一个BspMI酶切位点；对扩增的基因组DNA进行酶切位点分析证实了他在该突变上的杂合性。在本研究中检测的所有5名成人/慢性型患者中都发现了一个51位异亮氨酸（ATC）突变为苏氨酸（ACC）的突变。它产生了一个SauI酶切位点，酶切位点分析证实4名患者是该突变的纯合突变体。另一名患者是该突变与另一个457位精氨酸（CGA）突变为谷氨酰胺（CAA）突变的复合杂合子。这些突变基因在由腺病毒 - SV40重组体转化的β-半乳糖苷酶缺陷的人成纤维细胞中表达出明显降低或完全缺乏的酶活性。我们得出结论，GM1神经节苷脂贮积症中的基因突变是异质性的，但51位异亮氨酸（ATC）突变为苏氨酸（ACC）的突变在日本成人/慢性病例中很常见。本文还简要讨论了GM1神经节苷脂贮积症中的基因型 - 表型相关性。
