van Reeuwijk Jeroen, Maugenre Svetlana, van den Elzen Christa, Verrips Aad, Bertini Enrico, Muntoni Francesco, Merlini Luciano, Scheffer Hans, Brunner Han G, Guicheney Pascale, van Bokhoven Hans
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hum Mutat. 2006 May;27(5):453-9. doi: 10.1002/humu.20313.
The importance of O-glycosylation of alpha-dystroglycan (alpha-DG) is evident from the identification of POMT1 mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity. WWS patients are characterized by congenital muscular dystrophy (CMD) with severe brain and eye abnormalities. This suggests a crucial role for alpha-DG during development of these organs and tissues. Here we report new POMT1 mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygous POMT1 mutations in four unrelated families that result in a less severe phenotype than WWS, characterized by CMD with calf hypertrophy, microcephaly, and mental retardation. Compared to WWS patients, these patients have milder structural brain abnormalities, and eye abnormalities were absent, except for myopia in some cases. In these patients we postulate that one or both transcripts for POMT1 confer residual protein O-mannosyltransferase activity. Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations.
α-肌营养不良蛋白（α-DG）O-糖基化的重要性从沃克-沃尔堡综合征（WWS）中POMT1突变的鉴定中可见一斑。大约五分之一的WWS患者显示出POMT1突变，这导致蛋白质甘露糖基转移酶活性完全丧失。WWS患者的特征是先天性肌营养不良（CMD）并伴有严重的脑和眼异常。这表明α-DG在这些器官和组织的发育过程中起关键作用。在此我们报告WWS患者中的新POMT1突变和多态性。此外，我们报告了四个不相关家族中不同的复合杂合POMT1突变，这些突变导致的表型比WWS轻，其特征为CMD伴有小腿肥大、小头畸形和智力迟钝。与WWS患者相比，这些患者的脑结构异常较轻，除了在某些情况下有近视外没有眼异常。在这些患者中我们推测POMT1的一个或两个转录本赋予了残余的蛋白质O-甘露糖基转移酶活性。我们的数据表明存在由POMT1突变导致的包括脑和眼异常的CMD疾病谱。
