Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)
Molecular basis of variant pseudo-Hurler polydystrophy (mucolipidosis IIIC)
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DOI：
10.1172/jci5826
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发表时间：
2000-03-01
影响因子：
15.9
通讯作者：
Canfield, WM
中科院分区：
文献类型：
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作者：
Raas-Rothschild, A;Cormier-Daire, V;Canfield, WM
粘脂沉积症 IIIC，或变异型假性 Hurler 多营养不良症，是一种溶酶体水解酶运输的常染色体隐性遗传疾病。与相关疾病粘脂沉积症 II 和 IIIA 不同，粘脂沉积症 IIIC 中受影响的酶（N-乙酰葡糖胺-1-磷酸转移酶 [GlcNAc-磷酸转移酶]）保留了对合成底物的全部转移酶活性，但缺乏对溶酶体水解酶的活性。最近，牛 GlcNAc 磷酸转移酶被分离为多亚基酶，其亚基结构为 α(2)β(2)gamma(2)。我们克隆了人类 γ 亚基的 cDNA，并将其基因定位于染色体 16p。我们还表明，在表现出这种疾病的大型多重德鲁兹家族中，MLIIIC 也映射到该染色体区域。对来自 3 个家族的患者的 γ 亚基 cDNA 进行序列分析，发现 γ 亚基密码子 167 处存在移码突变，该突变与疾病分离，表明 MLIIIC 是磷酸转移酶 γ 亚基基因突变的结果。据我们所知，这是对人类粘脂沉积症分子基础的首次描述，并表明γ亚基在溶酶体水解酶识别中发挥作用。
Mucolipidosis IIIC, or variant pseudo-Hurler polydystrophy, is an autosomal recessive disease of lysosomal hydrolase trafficking. Unlike the related diseases, mucolipidosis II and IIIA, the enzyme affected in mucolipidosis IIIC (N-Acetylglucosamine-1-phosphotransferase [GlcNAc-phosphotransferase]) retains full transferase activity on synthetic substrates but lacks activity on lysosomal hydrolases. Bovine GlcNAc-phosphotransferase has recently been isolated as a multisubunit enzyme with the subunit structure alpha(2)beta(2)gamma(2). We cloned the cDNA for the human gamma-subunit and localized its gene to chromosome 16p. We also showed, in a large multiplex Druze family that exhibits this disorder, that MLIIIC also maps to this chromosomal region. Sequence analysis of the gamma-subunit cDNA in patients from 3 families identified a frameshift mutation, in codon 167 of the gamma subunit, that segregated with the disease, indicating MLIIIC results from mutations in the phosphotransferase gamma-subunit gene. This is to our knowledge the first description of the molecular basis for a human mucolipidosis and suggests that the gamma subunit functions in lysosomal hydrolase recognition.