title: Myotubularin-related 2 protein phosphatase and neurofilament light chain protein, both mutated in CMT neuropathies, interact in peripheral nerve.
abstract: 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.
authors.affiliation: Neuropathology Unit, Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Previtali
authors.forename: Barbara
authors.initials: B
authors.lastname: Zerega
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.forename: Rosalind H M
authors.initials: RH
authors.lastname: King
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Salih
authors.forename: Laura
authors.initials: L
authors.lastname: Feltri
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Monaco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L; C408986:MTMR2 protein, human; C498717:Mtmr2 protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor