title: Multiple disease-linked myotubularin mutations cause NFL assembly defects in cultured cells and disrupt myotubularin dimerization.
abstract: Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy that has been linked to mutations in multiple genes. Mutations in the neurofilament light (NFL) chain gene lead to the CMT2E form whereas mutations in the myotubularin-related protein 2 and 13 (MTMR2 and MTMR13) genes lead to the CMT4B form. These two forms share characteristic pathological hallmarks on nerve biopsies including concentric sheaths ('onion bulbs') and, in at least one case, myelin loops. In addition, MTMR2 protein has been shown to interact physically with both NFL and MTMR13. Here, we present evidence that CMT-linked mutations of MTMR2 can cause NFL aggregation in a cell line devoid of endogenous intermediate filaments, SW13vim(-). Mutations in the protein responsible for X-linked myotubular myopathy (myotubularin, MTM1) also induced NFL abnormalities in these cells. We also show that two MTMR2 mutant proteins, G103E and R283W, are unable to form dimers and undergo phosphorylation in vivo, implicating impaired complex formation in myotubularin-related pathology.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians & Surgeons, New York, New York 10032, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Goryunov
authors.forename: Andrew
authors.initials: A
authors.lastname: Nightingale
authors.forename: Lorelei
authors.initials: L
authors.lastname: Bornfleth
authors.forename: Conrad
authors.initials: C
authors.lastname: Leung
authors.forename: Ronald K H
authors.initials: RK
authors.lastname: Liem
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D019281:Dimerization; D006801:Humans; D016296:Mutagenesis; D016900:Neurofilament Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014162:Transfection
chemical_list: D016900:Neurofilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012694:Serine; C044882:neurofilament protein L; C051774:neurofilament protein H; C061195:neurofilament protein M; C408986:MTMR2 protein, human; C475072:SBF2 protein, human; C099588:myotubularin