Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies
Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies
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DOI：
10.1016/j.ajhg.2009.06.006
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发表时间：
2009-07-10
影响因子：
9.8
通讯作者：
Wevers, Ron A.
中科院分区：
文献类型：
--
作者：
Lefeber, Dirk J.;Schoenberger, Johannes;Wevers, Ron A.
α -糖营养不良症，如Walker Warburg综合征，是肌营养不良症的一个重要亚群，与α -糖营养不良的o -甘露糖基化缺陷有关。在许多患者中，潜在的遗传病因仍未解决。孤立性肌营养不良尚未在先天性糖基化障碍（CDG）中被描述，这是由n -连接蛋白糖基化缺陷引起的。在这里，我们提出了遗传性n -糖基化障碍与肌肉营养不良的CDG i型组。广泛的生化研究显示，dolol -磷酸-甘露糖（dolp -man）合成酶活性强烈降低。对三个DPM亚基的测序和DPM3缺失的CHO2.38细胞的互补显示，在DPM3强保守的线圈结构域（将催化DPM1束缚在ER膜上）存在致病性p.L85S错义突变。CHO细胞共转染实验显示，DPM3（L85S）对DPM1的结合能力降低。对内质网中四种dole - p -man依赖的糖基化途径的研究显示，肌肉活检中α -肌营养不良聚糖的o -甘露糖基化强烈减少，从而解释了肌营养不良的临床表型。这种由DPM3突变引起的轻度dolp - man生物合成缺陷是α -糖代谢异常的一个原因，因此将先天性糖基化障碍与糖代谢异常联系起来。
Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glycosylation defects. Here, we present a genetic N-glycosylation disorder with muscular dystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L85S) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies.