Muscle-eye-brain disease (MEB) and Walker Warburg Syndrome (WWS) belong to a spectrum of autosomal recessive diseases characterized by ocular dysgenesis, neuronal migration defects, and congenital muscular dystrophy. Until now, the pathophysiology of MEB/WWS has been attributed to alteration in dystroglycan post-translational modification. Here, we provide evidence that mutations in a gene coding for a major basement membrane protein, collagen IV alpha 1 (COL4A1), are a novel cause of MEB/WWS. Using a combination of histological, molecular, and biochemical approaches, we show that heterozygous Col4a1 mutant mice have ocular dysgenesis, neuronal localization defects, and myopathy characteristic of MEB/WWS. Importantly, we identified putative heterozygous mutations in COL4A1 in two MEB/WWS patients. Both mutations occur within conserved amino acids of the triple-helix-forming domain of the protein, and at least one mutation interferes with secretion of the mutant proteins, resulting instead in intracellular accumulation. Expression and posttranslational modification of dystroglycan is unaltered in Col4a1 mutant mice indicating that COL4A1 mutations represent a distinct pathogenic mechanism underlying MEB/WWS. These findings implicate a novel gene and a novel mechanism in the etiology of MEB/WWS and expand the clinical spectrum of COL4A1-associated disorders.
Muscle-eye-brain disease (MEB) and Walker-Warburg Syndrome (WWS) are devastating childhood diseases that belong to a subgroup of congenital muscular dystrophies (CMDs) characterized by ocular dysgenesis, neuronal migration defects, and congenital myopathy. Genetic studies have revealed a number of genes involved in the etiology of CMDs, and subsequent studies show that alterations in dystroglycan glycosylation underlie MEB/WWS. However, over half of MEB/WWS patients do not have mutations in known genes encoding glycosyltransferases, suggesting that other genes are involved. Here, we describe a novel and genetically complex mouse model for MEB/WWS and identify putative heterozygous mutations in COL4A1 in two MEB/WWS patients. We identify a novel gene implicated in the etiology of MEB/WWS, provide evidence of mechanistic heterogeneity for this subgroup of congenital muscular dystrophies, and develop an assay to test the functional significance of putative COL4A1 mutations. Our findings represent the first evidence for a dominant mutation leading to MEB/WWS–like diseases and expand the spectrum of clinical disorders resulting from Col4a1/COL4A1 mutations.