Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie)
Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie)
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DOI：
10.1172/jci7302
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发表时间：
2000-01-01
影响因子：
15.9
通讯作者：
Freeze, HH
中科院分区：
文献类型：
--
作者：
Kim, S;Westphal, V;Freeze, HH
先天性糖基化障碍(CDGs)是糖蛋白生物合成的代谢缺陷，通常会导致严重的精神和精神运动发育迟缓。通过改变血清转铁蛋白(Tf)的等电聚焦(IEF)模式，可以识别不同形式的CDG。通过[2-H-3]甘露糖对成纤维细胞的代谢标记，分析了2例具有这些症状和相似异常的TfIEF模式的患者。患者产生了一个截短的二羟甲基二醇连接的前体低聚糖，含有5个甘露糖残基，而不是正常的含有9个甘露糖残基的前体。在培养基中添加250亩甘露糖，可使截短的低聚糖的大小得到纠正。这些患者的成纤维细胞中的微粒体大约95%缺乏Dol-P-Man合酶活性，GDP-Man的表观K-m类似于正常的6倍。编码Dol-P-Man合成酶催化亚单位的基因DPM1在两个患者中都发生了改变。1例患者发生C(274)G点突变，导致编码序列R(92)G改变。另一名患者也有C274G突变和13个碱基的缺失，这可能导致了不稳定的转录本。DPM1的缺陷定义了一种新的糖基化紊乱，CDG-ie。
Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin (Tf). Two patients with these symptoms and similar abnormal TfIEF patterns were analyzed by metabolic labeling of fibroblasts with [2-H-3]mannose. The patients produced a truncated dolichol-linked precursor oligosaccharide with 5 mannose residues, instead of the normal precursor with 9 mannose residues. Addition of 250 mu M mannose to the culture medium corrected the size of the truncated oligosaccharide. Microsomes from fibroblasts of these patients were approximately 95% deficient in dolichol-phosphate-mannose (Dol-P-Man) synthase activity, with an apparent K-m for GDP-Man similar to 6-fold higher than normal. DPM1, the gene coding for the catalytic subunit of Dol-P-Man synthase, was altered in both patients. One patient had a point mutation, C(274)G, causing an R(92)G change in the coding sequence. The other patient also had the C274G mutation and a 13-bp deletion that presumably resulted in an unstable transcript. Defects in DPM1 define a new glycosylation disorder, CDG-Ie.