The Expanding Phenotype ofPOMT1Mutations: From Walker-Warburg Syndrome to Congenital Muscular Dystrophy, Microcephaly, and Mental Retardation

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Abstract

The importance of O-glycosylation of alpha-dystroglycan (α-DG) is evident from the identification ofPOMT1mutations in Walker-Warburg syndrome (WWS). Approximately one-fifth of the WWS patients show mutations inPOMT1, 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 α-DG during development of these organs and tissues. Here we report newPOMT1mutations and polymorphisms in WWS patients. In addition, we report different compound heterozygousPOMT1mutations 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 fromPOMT1mutations. Hum Mutat 27(5), 453-459, 2006. © 2006 Wiley-Liss, Inc.

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