A Comparative Study of α-Dystroglycan Glycosylation in Dystroglycanopathies Suggests that the Hypoglycosylation of α-Dystroglycan Does Not Consistently Correlate with Clinical Severity
A Comparative Study of α-Dystroglycan Glycosylation in Dystroglycanopathies Suggests that the Hypoglycosylation of α-Dystroglycan Does Not Consistently Correlate with Clinical Severity
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DOI：
10.1111/j.1750-3639.2008.00198.x
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发表时间：
2009-10-01
期刊：
影响因子：
6.4
通讯作者：
Muntoni, Francesco
中科院分区：
文献类型：
--
作者：
Jimenez-Mallebrera, Cecilia;Torelli, Silvia;Muntoni, Francesco
α-肌营养不良蛋白聚糖的低糖基化是肌营养不良症亚组的基础，其范围从先天性虚弱发作、严重脑畸形和围产期死亡到成年期轻度虚弱而无脑受累。在一定比例的患者中发现了6个基因的突变。POMT 1、POMT 2和POMGnT 1编码参与α-肌营养不良聚糖甘露糖基化的糖基转移酶，但fukaline、FKRP和LARGE的功能尚不清楚。病理学标志是骨骼肌的免疫标记减少，抗体识别α-肌营养不良蛋白聚糖上的糖基化表位。如果这些疾病的共同途径是α-肌营养不良聚糖的低糖基化，则可以预期临床严重程度与低糖基化程度之间存在相关性。通过研究24例这些基因突变的患者，我们发现POMT 1、POMT 2和POMGnT 1突变患者的α-肌营养不良蛋白聚糖染色减少与临床病程之间存在良好的相关性。然而，这并不总是在fukalin和FKRP缺陷的患者中的情况，因为我们鉴定了具有轻度肢带表型而没有脑受累的患者，其α-肌营养不良聚糖严重缺失。这些数据表明，并不总是可能将临床病程与α-肌营养不良聚糖标记相关联，并表明这些疾病中α-肌营养不良聚糖加工可能存在差异。
Hypoglycosylation of alpha-dystroglycan underpins a subgroup of muscular dystrophies ranging from congenital onset of weakness, severe brain malformations and death in the perinatal period to mild weakness in adulthood without brain involvement. Mutations in six genes have been identified in a proportion of patients. POMT1, POMT2 and POMGnT1 encode for glycosyltransferases involved in the mannosylation of alpha-dystroglycan but the function of fukutin, FKRP and LARGE is less clear. The pathological hallmark is reduced immunolabeling of skeletal muscle with antibodies recognizing glycosylated epitopes on alpha-dystroglycan. If the common pathway of these conditions is the hypoglycosyation of alpha-dystroglycan, one would expect a correlation between clinical severity and the extent of hypoglycosylation. By studying 24 patients with mutations in these genes, we found a good correlation between reduced alpha-dystroglycan staining and clinical course in patients with mutations in POMT1, POMT2 and POMGnT1. However, this was not always the case in patients with defects in fukutin and FKRP, as we identified patients with mild limb-girdle phenotypes without brain involvement with profound depletion of alpha-dystroglycan. These data indicate that it is not always possible to correlate clinical course and alpha-dystroglycan labeling and suggest that there might be differences in alpha-dystroglycan processing in these disorders.