title: COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans.
abstract: 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.
authors.affiliation: Departments of Ophthalmology and Anatomy, Institute for Human Genetics, University of California San Francisco School of Medicine, San Francisco, California, United States of America.
authors.forename: Cassandre
authors.initials: C
authors.lastname: Labelle-Dumais
authors.forename: David J
authors.initials: DJ
authors.lastname: Dilworth
authors.forename: Emily P
authors.initials: EP
authors.lastname: Harrington
authors.forename: Michelle
authors.initials: M
authors.lastname: de Leau
authors.forename: David
authors.initials: D
authors.lastname: Lyons
authors.forename: Zhyldyz
authors.initials: Z
authors.lastname: Kabaeva
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D005123:Eye / Q000473:pathology*; D006801:Humans; D051379:Mice; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000473:pathology*; D016415:Sequence Alignment; D058494:Walker-Warburg Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV