Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase.
Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase.
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德系犹太裔患者成人发病和慢性 GM2 神经节苷脂增多症的分子基础：β-己糖胺酶 α 亚基的 269 位丝氨酸取代甘氨酸。
DOI：
10.1073/pnas.86.7.2413
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发表时间：
1989
影响因子：
11.1
通讯作者：
Neufeld,EF
中科院分区：
文献类型：
--
作者：
Paw,BH;Kaback,MM;Neufeld,EF
慢性和成人发病的GM2神经节苷脂疾病是由β-氨基己糖苷酶A同工酶显著缺乏引起的神经系统疾病；它们发生在德系犹太人人群中，虽然比典型的(婴儿)泰-萨克斯病发生率较低。早期的生物合成研究已经发现了一个缺陷的阿尔法亚基，它无法与贝塔亚基联系在一起。我们现在已经在外显子7的3‘端发现了鸟苷到腺苷的转变，这导致了阿尔法亚单位269位的丝氨酸替代甘氨酸[指定为269(Gly-Ser)替代]。核糖核酸酶保护试验被用来定位突变到一名成人起病患者的成纤维细胞中的一段mRNA。用聚合酶链式反应扩增该片段(逆转录后)和相应的基因组DNA片段，并用双脱氧法进行测序。序列分析和基于ScrFI酶切位点缺失的分析表明，患者是一名复合杂合子，从父亲那里遗传了269(Gly-Ser)突变，从母亲那里遗传了等位基因零突变。在具有关联缺陷表型的胎儿成纤维细胞和5例慢性GM2神经节苷脂沉积症患者的细胞中，也发现了269(Gly-Ser)突变，其杂合性可能为零等位基因。在婴儿泰-萨克斯病患者的β-氨基己糖苷酶A缺乏的细胞中没有发现它，在没有β-氨基己糖苷酶A缺陷的人的细胞中也没有发现。然而，肯定还有其他具有类似后果的突变，因为269(Gly-Ser)替换不存在于两名幼年型GM2神经节苷脂沉着症患者的成纤维细胞中，尽管这些突变具有关联缺陷的阿尔法亚单位。
Chronic and adult-onset GM2 gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of beta-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective alpha-subunit that failed to associate with the beta-subunit. We have now found a guanosine to adenosine transition at the 3' end of exon 7, which causes substitution of serine for glycine at position 269 of the alpha-subunit [designated 269 (Gly----Ser) substitution]. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly----Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly----Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic GM2 gangliosidosis. It was not found in beta-hexosaminidase A-deficient cells obtained from patients with infantile Tay-Sachs disease nor in cells from individuals who do not have beta-hexosaminidase A deficiency. However, there must be additional mutations with similar consequences, since the 269 (Gly----Ser) substitution was not present in fibroblasts from two patients with juvenile GM2 gangliosidosis even though these had an association-defective alpha-subunit.
影响因子：
4.3
作者：
H. Sambrook
通讯作者：
H. Sambrook