Unravelling the molecular basis of CMT4B pathology

• Published in: Journal of the peripheral nervous system Vol. 9; no. 2; p. 125
• Main Authors: Bolis, A, Previtali, S, Bussini, S, Dina, G, Dati, G, Feltri, ML, Quattrini, A, Wrabetz, L, Bolino, A
• Format: Journal Article
• Language: English
• Published: Oxford, UK; Malden, USA Blackwell Science Inc 01.06.2004
• ISSN: 1085-9489; 1529-8027
• DOI: 10.1111/j.1085-9489.2004.009209bq.x

Charcot‐Marie‐Tooth type 4B (CMT4B) disease is a severe autosomal recessive peripheral neuropathy with childhood onset, characterised by progressive muscular atrophy and weakness in the distal extremities, sensory loss, severely decreased nerve conduction velocities, and demyelination with myelin outfoldings in the peripheral nerve. We demonstrated that CMT4B is caused by loss of function mutations in the Myotubularin‐related 2 gene, MTMR2, on chromosome 11q22 (Bolino et al., Nat Genet 25:17–19, 2000). MTMR2 belongs to the myotubularin family of protein phosphatases, of which, myotubularin (MTM), mutated in the X‐linked myotubular myopathy (XLMTM) is the founder member. MTMR2 shows specific activity towards phosphatidylinositol 3‐phosphate and 3,5‐biphosphate, PI(3)P and PI(3,5)P2, respectively. However, how abrogation of this lipid phosphatase activity is leading to the specific disease phenotype has not yet been demonstrated. To elucidate the biological role of MTMR2 in the nerve, we performed an extensive expression analysis of this protein in the peripheral nervous system. Since MTMR2 was demonstrated to be ubiquitously expressed also within the nerve, we sought nerve‐specific interactors using the yeast two‐hybrid approach. The neurofilament light chain protein, NF‐L, mutated in various CMTs including axonal type CMT2E, and demyelinating Dejerine‐Sottas syndrome, was found to interact with MTMR2 in Schwann cells as well as in neurons. Since NF‐L is specifically expressed in the nervous system, the interaction between MTMR2 and NF‐L would explain why loss of a ubiquitously expressed phosphatase affects specifically the nerve (Previtali and Bolino, Hum Mol Genet 12:1713–1723, 2003). To model the CMT4B pathology, we generated a general knock‐out mouse arising from inactivation f Mtmr2 in all cells. The characterisation of this animal model is underway. Overall, Mtmr2 null mice display a milder phenotype with respect to the human disorder. The morphological analysis of the peripheral nerve of this mouse line performed at P28 revealed the presence of myelin outfoldings, which are the hallmark of CMT4B pathology.