Abstract
Intragenic homozygous deletions in the
Large
gene are associated with a severe neuromuscular phenotype in the myodystrophy (
myd
) mouse. These mutations result in a virtual lack of glycosylation of α-dystroglycan. Compound heterozygous
LARGE
mutations have been reported in a single human patient, manifesting with mild congenital muscular dystrophy (CMD) and severe mental retardation. These mutations are likely to retain some residual LARGE glycosyltransferase activity as indicated by residual α-dystroglycan glycosylation in patient cells. We hypothesized that more severe
LARGE
mutations are associated with a more severe CMD phenotype in humans. Here we report a 63-kb intragenic
LARGE
deletion in a family with Walker-Warburg syndrome (WWS), which is characterized by CMD, and severe structural brain and eye malformations. This finding demonstrates that
LARGE
gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the α-dystroglycan protein.