Muscle eye brain disease (MEB) and Walker Warburg syndrome (WWS) are among a spectrum of rare congenital muscular dystrophies (CMDs) that are inherited in an autosomal recessive pattern and are characterised by variable eye, brain and muscular defects. The cause of disease in a proportion of patients has been attributed to defects in the post-translational modification of dystroglycans, but Labelle-Dumais et al. now report a newly identified and distinct molecular defect that can also cause MEB and WWS. Their results show that mutations in the gene encoding basement membrane protein collagen IV α1 (COL4A1) are associated with these disorders in two patients, and that Col4a1 heterozygous mice have defects resembling symptoms observed in humans with MEB and WWS. Molecular analyses support the previous hypothesis that COL4A1 mutations cause toxic intracellular accumulation of the mutant protein, although further studies are required to rule out other pathomechanisms. These results provide evidence that COL4A1 mutations can cause inherited CMD spectrum disorders in a dominant manner, and shed light on the role of this basement membrane protein in normal and disease physiology.
Labelle-Dumais C., Dilworth D. J., Harrington E. P., de Leau M., Lyons D., Kabaeva Z., Manzini M. C., Dobyns W. B., Walsh C. A., Michele D. E., et al. (2011). COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans PLoS Genet. 7, e1002062.
