Human Molecular Genetics, 2003, Vol. 12, No. 14 1713-1723
DOI: 10.1093/hmg/ddg179
© 2003 Oxford University Press
Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve
1Neuropathology Unit, Department of Neurology, San Raffaele Scientific Institute, 20132 Milano, Italy, 2Laboratory of Molecular Genetics, Gaslini Institute and Dulbecco Telethon Institute, 16148 Genova, Italy, 3Department of Preclinical Veterinary Sciences, University of Edinburgh, Edinburgh EH9 1QH, UK, 4Department of Clinical Neurosciences, Royal Free and University College School of Medicine, Rowland Hill Street, London NW3 2PF, UK, 5Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia, 6DIBIT, San Raffaele Scientific Institute, 20132 Milano, Italy, 7Laboratory of Molecular Genetics, Gaslini Institute and Department of Pediatrics and CEBR, University of Genova, Genova, Italy and 8Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Received March 17, 2003; Accepted May 9, 2003
Charcot–Marie–Tooth disease type 4B1, CMT4B1, is a severe, autosomal-recessive, demyelinating peripheral neuropathy, due to mutations in the Myotubularin-related 2 gene, MTMR2. MTMR2 is widely expressed and encodes a phosphatase whose substrates include phosphoinositides. However, this does not explain how MTMR2 mutants specifically produce demyelination in the peripheral nerve. Therefore, we analysed the cellular and subcellular distribution of Mtmr2 in nerve. Mtmr2 was detected in all cytoplasmic compartments of myelin-forming Schwann cells, as well as in the cytoplasm of non-myelin-forming Schwann cells and both sensory and motorneurons. In contrast, Mtmr2 was detected in the nucleus of Schwann cells and motorneurons, but not in the nucleus of sensory neurons. As Mtmr2 is diffusely present also within the nerve, a specific function could derive instead from nerve-specific interacting proteins. Therefore, we performed two yeast two-hybrid screenings, using either fetal brain or peripheral nerve cDNA libraries. The neurofilament light chain protein, NF-L, was identified repeatedly in both screenings, and found to interact with MTMR2 in both Schwann cells and neurons. Interestingly, NF-L, encoding NF-L, is mutated in CMT2E. These data may provide a basis for the nerve-specific pathogenesis of CMT4B1, and further support for the notion that hereditary demyelinating and axonal neuropathies may represent different clinical manifestations of a common pathological mechanism.
* To whom correspondence should be addressed at: Laboratory of Molecular Genetics, Gaslini Institute, Largo Gaslini 5, 16148 Genova, Italy. Tel: +39 0105636403; Fax: +39 0103779797; Email: bolino{at}unige.it or bolino.alessandra{at}hsr.it
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