FUNCTIONAL ANALYSIS OF THE MYOTUBULARIN-RELATED-2 GENE, MTMR2, RESPONSIBLE FOR CHARCOT-MARIE-TOOTH TYPE 4B DISEASE

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, generally characterised by progressive muscular atrophy and weakness with sensory loss, occurring in the distal extremities. The age of onset is usually between the first and the second decade of life. Among the different forms of CMT, Charcot-Marie-Tooth type 4B (CMT4B) represents an autosomal recessive demyelinating neuropathy characterised by infantile onset with progressive symmetric distal and proximal weakness starting in the lower extremities, cranial nerve involvement in most of the cases, and focally folded myelin sheaths in the peripheral nerve. A first locus for CMT4B has been mapped on chromosome 11q22. Two years ago, I undertook a project aimed to identify this gene on chromosome 11, using a positional cloning strategy. The CMT4B gene was isolated and mutations were demonstrated in CMT4B patients occurring in the MTMR2 gene, encoding the Myotubularin related protein 2. This gene belongs to a family of at least 20 genes, showing high homology with myotubularin, the first member to be identified. The myotubularin related proteins are phosphatases which are able to remove phosphate residues from other proteins that are involved in the control of gene expression or cell growth/differentiation. MTMR2 is the first phosphatase to be isolated as responsible for a peripheral neuropathy. This project is aimed to elucidate the pathogenetic mechanisms behind CMT4B, following three main lines of research: 1) identification of a SET-containing protein interacting with MTMR2; 2) localisation of MTMR2 in the peripheral nerve; 3) generation of animal models to clarify the role of MTMR2 in peripheral nerve development and myelination.