FUNCTIONAL CHARACTERIZATION OF HYCCIN, A NOVEL MEMBRANE PROTEIN INVOLVED IN CENTRAL AND PERIPHERAL MYELINATION

“White-matter disorders” (WMDs) constitute a heterogeneous group of genetic and acquired diseases predominantly affecting the white matter of the brain. In the last decade, the genetic etiology of several WMDs has been elucidated. Nevertheless about half of the cases remains without a specific diagnosis. The largest single category among the unclassified WMDs is constituted by the cases with hypomyelination. Recently we identified a novel autosomal recessive WMD, which we called “Hypomyelination and Congenital Cataract” (HCC), in five unrelated families with ten subjects affected by congenital cataract, progressive neurological impairment and evidence of diffuse myelin deficiency on magnetic resonance of the brain and in peripheral nerve biopsy. We mapped the gene and identified three mutations in a novel gene, DRCTNNB1A. The function of the protein encoded by this gene, named hyccin, is still unknown. However, we showed that hyccin is a novel protein which is essential for central and peripheral myelination. The main goal of this project is to characterize hyccin biological functions through the following steps:1) study of the mechanisms of action of hyccin in a cell system with particular attention to the possible connection between hyccin and signaling pathways known to regulate myelinogenesis; 2) analysis of hyccin role in other WMDs; 3) search for hyccin-interacting proteins ; 4) creation and analysis of a genetically modified mouse model with deficit of hyccin Our study will define the pathogenetic role of hyccin in hypomyelinating disorders of unknown etiology and will determine the cellular function of hyccin, clarifying its role in the central and peripheral myelination.