MUTATIONS IN THE GLUCOSE-6-PHOSPHATASE GENE ARE ASSOCIATED WITH GLYCOGEN-STORAGE-DISEASE TYPES 1A AND 1ASP BUT NOT 1B AND 1C
MUTATIONS IN THE GLUCOSE-6-PHOSPHATASE GENE ARE ASSOCIATED WITH GLYCOGEN-STORAGE-DISEASE TYPES 1A AND 1ASP BUT NOT 1B AND 1C
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DOI：
10.1172/jci117645
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发表时间：
1995-01-01
影响因子：
15.9
通讯作者：
CHOU, JY
中科院分区：
文献类型：
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作者：
LEI, KJ;SHELLY, LL;CHOU, JY
糖原贮积病（GSD）1型是由葡萄糖6磷酸酶（G6Pase）缺乏引起的，是一种具有异质性症状的常染色体隐性遗传疾病，已提出两种G6Pase催化模型来解释观察到的异质性。转位酶催化单元模型提出存在五个 GSD 1 型亚组，它们对应于 G6Pase 催化单元 (1a)、稳定蛋白 (1aSP)、葡萄糖-6-P (1b)、磷酸盐/焦磷酸盐 (1c) 和葡萄糖 (1d) 转位酶中的缺陷。相反，构象-底物-转运模型表明，G6Pase 是一种单一的多功能膜通道蛋白，具有催化和底物（或产物）转运活性。我们最近证明，G6Pase 催化单元的突变会导致 1a 型 GSD。为了阐明 G6Pase 基因突变是否与其他 GSD 1 型亚组有关，我们对 1b、1c 和 1aSP 型 GSD 患者的 G6Pase 基因进行了表征。结果表明，1b 和 1c 型 GSD 患者的 G6Pase 基因是正常的，与 G6Pase 催化的转位酶催化单元模型一致。然而，在 1aSP 型患者的两个 G6Pase 等位基因中发现了外显子 2 中的突变，该突变将密码子 83 处的 Arg 转换为 Cys (R83C)。 R83C突变也在一名纯合子和五名异源GSD 1a型患者中得到证实，表明1aSP型是GSD 1a型的错误分类。我们还分析了另外 7 名 1a 型患者的 G6Pase 基因，发现了两种导致 1a 型 GSD 的新突变。
Glycogen storage disease (GSD) type 1, which is caused by the deficiency of glucose-6-phosphatase (G6Pase), is an autosomal recessive disease with heterogenous symptoms, Two models of G6Pase catalysis have been proposed to explain the observed heterogeneities. The translocase-catalytic unit model proposes that five GSD type 1 subgroups exist which correspond to defects in the G6Pase catalytic unit (1a), a stabilizing protein (1aSP), the glucose-6-P (1b), phosphate/pyrophosphate (1c), and glucose (1d) translocases. Conversely, the conformation-substrate-transport model suggests that G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities, We have recently demonstrated that mutations in the G6Pase catalytic unit cause GSD type 1a. To elucidate whether mutations in the G6Pase gene are responsible for other GSD type 1 subgroups, we characterized the G6Pase gene of GSD type 1b, 1c, and 1aSP patients, Our results show that the G6Pase gene of GSD type 1b and 1c patients is normal, consistent with the translocase-catalytic unit model of G6Pase catalysis. However, a mutation in exon 2 that converts an Arg at codon 83 to a Cys (R83C) was identified in both G6Pase alleles of the type 1aSP patient. The R83C mutation was also demonstrated in one homozygous and five heterogenous GSD type la patients, indicating that type 1aSP is a misclassification of GSD type 1a. We have also analyzed the G6Pase gene of seven additional type 1a patients and uncovered two new mutations that cause GSD type 1a.