The congenital
muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative
glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of
alpha-dystroglycan.
Fukuyama CMD,
muscle-eye-brain disease and
Walker-Warburg syndrome, each associated with
eye abnormalities and neuronal migration defects, result from mutations in fukutin,
POMGnT1 and POMT1, respectively, while mutations in the fukutin-related
protein (FKRP) gene cause congenital
muscular dystrophy 1C, typically lacking brain involvement. Another putative
glycosyltransferase, Large, is mutated in the
myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of
muscular dystrophy. We studied 36 patients with
muscular dystrophy and either
mental retardation, structural brain changes or abnormal
alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital
muscular dystrophy, profound
mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of
alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated
epitope demonstrated a reduced molecular weight form of
alpha-dystroglycan that retained some
laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.