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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 α-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 α-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 α-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of α-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.

human molecular genetics

Mutations in the human  LARGE  gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of α-dystroglycan