title: Is a novel I214M substitution in the NEFL gene a cause of Charcot-Marie-Tooth disease? Functional analysis using cell culture models.
abstract: Recent studies have shown that mutations in neurofilament light subunit gene (NEFL) cause Charcot-Marie-Tooth (CMT) disease. Since the first description of the Gln333Pro mutation in the NEFL gene, 10 pathogenic mutations in the NEFL gene have been reported in patients affected with CMT disease. We report a novel I214M amino acid substitution in the NEFL gene in two unrelated patients affected with CMT. Because the I214M amino acid substitution in the NEFL protein was not detected in a CMT affected brother of the proband, its pathogenic effect became unclear. In order to determine whether this amino acid substitution is a benign polymorphism or causative of the disease, we performed a functional analysis of the mutant I214M neurofilament protein (NFL). Transfections of the mutant protein in cultured cells revealed an increased tendency to form highly compacted filamentous structures but no other alterations of neurofilament assembly or transport were observed. Furthermore, the sibling of one of the patients was also affected with CMT but did not have the I214M substitution. These data suggest that this I214M substitution in the NEFL gene was not a direct cause of the disease but could be a polymorphism or possibly a modifier of the CMT phenotype.
authors.affiliation: Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Kabzińska
authors.forename: Raul
authors.initials: R
authors.lastname: Perez-Olle
authors.forename: Dmitry
authors.initials: D
authors.lastname: Goryunov
authors.forename: Hanna
authors.initials: H
authors.lastname: Drac
authors.forename: Barbara
authors.initials: B
authors.lastname: Ryniewicz
authors.forename: Irena
authors.initials: I
authors.lastname: Hausmanowa-Petrusewicz
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochański
authors.forename: Ronald K H
authors.initials: RK
authors.lastname: Liem
mesh_terms: D000293:Adolescent; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D002277:Carcinoma; D045744:Cell Line, Tumor; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005260:Female; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D008297:Male; D008715:Methionine / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D014746:Vimentin / Q000378:metabolism
chemical_list: D016900:Neurofilament Proteins; D014746:Vimentin; C044882:neurofilament protein L; D007532:Isoleucine; D008715:Methionine