Homozygous dystroglycan mutation associated with a novel muscle–eye–brain disease-like phenotype with multicystic leucodystrophy

Abstract

Defects in dystroglycan post-translational modification result in congenital muscular dystrophy with or without additional eye and brain involvement, are referred to as secondary dystroglycanopathies and have been associated with mutations in 11 different genes encoding glycosyltransferases or associated proteins. However, only one patient with a mutation in the dystroglycan encoding gene DAG1 itself has been described before. We here report a homozygous novel DAG1 missense mutation c.2006G>T predicted to result in the amino acid substitution p.Cys669Phe in the β-subunit of dystroglycan in two Libyan siblings. The affected girls presented with a severe muscle-eye-brain disease-like phenotype with distinct additional findings of macrocephaly and extended bilateral multicystic white matter disease, overlapping with the cerebral findings in patients with megalencephalic leucoencephalopathy with subcortical cysts. This novel clinical phenotype observed in our patients further expands the clinical spectrum of dystroglycanopathies and suggests a role of DAG1 not only for dystroglycanopathies but also for some forms of more extensive and multicystic leucodystrophy.

Genetics and mechanisms leading to human cortical malformations

“…Rare mutations have been identified in this gene in WWS [208,209]. Dystroglycan (DG) is subjected to a post-translational cleavage to generate the peripheral membrane protein α-DG, and the transmembrane protein β-DG.…”

POMKmutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability

“…However, the exact glycan structures required for ligand binding and the enzymes involved in glycosylation have not yet been determined conclusively. Mutations in genes that are involved in the process of glycosylation cause the more frequent secondary dystroglycanopathies,2 in contrast with the rare occurrence of primary dystroglycanopathies by mutations of the dystroglycan coding gene DAG1 , which have only been described twice 3 4…”

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…The extracellular matrix receptor function of α-DG is impaired when either DAG1 is itself mutated (limb-girdle muscular dystrophy type 2P) (10,16,17) or genes that encode putative or known glycosyltransferases that act on α-DG are mutated (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, or limb-girdle muscular dystrophy) (12,18,19). Sarcolemmal expression of α-DG, sarcospan, and the sarcoglycan complex is reduced in patients with distinct sarcoglycan mutations (limb-girdle muscular dystrophy type 2C-F) (3)(4)(5)20).…”