Genetics of Walker-Warburg syndrome: A disorder of brain, muscle and eye development

Walker Warburg Syndrome is a rare autosomal recessive developmental disorder of the eye, muscle and brain. CNS abnormalities are characterized by the complete loss of gyri due to over-migration of cortical neurons. The purpose of this thesis was to investigate the genetics of Walker-Warburg syndrome (WWS). Through genome wide screen analysis of more than ten consanguineous families and we determined that WWS is a heterogeneous disorder. Our results indicate the existence of at least three loci.; Subsequently, we used a candidate gene approach. In collaboration with a group lead by Dr. Han Brunner, we identified mutations in the o-mannosyl transferase POMT1 in a small subset of WWS patients. In situ analysis of POMT1 revealed ubiquitous expression in muscle, eye and brain throughout mouse development. POMT1 mRNA labeling closely matched that of the hypothesized substrate of POMT1, alpha dystroglycan.; Sequence analysis of 30 consecutive, unselected, WWS patients revealed mutations in POMT1 in only two. Analysis of six WWS patients from consanguineous families ruled out linkage at the POMT1 locus. Together these data suggest that mutations in POMT1 are a rare cause of WWS.; The same sort of neuronal over-migration seen in WWS is also found in two other autosomal recessive disorders: Muscle Eye Brain (MEB) and Fukuyama Congenital Muscular Dystrophy (FCMD). Linkage and sequence analysis of the MEB gene, POMGnT1 and the FCMD gene, fukutin, in WWS patients revealed null mutations in each. This demonstrates clinical and genetic overlap between WWS, MEB and FCMD.; Through the clinical and radiologic study of 53 WWS patients diagnostic criteria for WWS were revised. Clinical and radiologic comparisons of WWS patients with and without mutations in POMT1 failed to reveal differences. From this work we conclude that POMGnT1, POMT1 and additional yet unidentified genes for WWS function in the same biochemical pathway to mannosylate proteins such as alpha-dystroglycan, critical for muscle, eye, brain development and neuronal migration.