The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation.
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.
van Reeuwijk
Jeroen
J
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Maugenre
Svetlana
S
van den Elzen
Christa
C
Verrips
Aad
A
Bertini
Enrico
E
Muntoni
Francesco
F
Merlini
Luciano
L
Scheffer
Hans
H
Brunner
Han G
HG
Guicheney
Pascale
P
van Bokhoven
Hans
H
D000293:Adolescent; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002675:Child, Preschool; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D018895:Microsatellite Repeats; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D011110:Polymorphism, Genetic; D013577:Syndrome
C483081:DAG1 protein, human; D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase