title: Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies.
abstract: Mutations in the myelin protein zero (MPZ) gene have been associated with different Charcot-Marie-Tooth disease (CMT) phenotypes, including classical demyelinating CMT1B and the axonal form of the disease (CMT2). The MPZ role in the pathogenesis of both demyelinating and axonal inherited neuropathies was evaluated in the Italian population by screening a cohort of 214 patients with CMT1 or CMT2. A MPZ mutation frequency of 7.9% in demyelinating cases and of 4.8% in axonal cases was observed. In the total cohort (264 patients), including those with mutations in other genes, a mutation frequency of 5.8% (7/121) in demyelinating cases and 4.2% (6/143) in axonal cases was found. Three novel MPZ mutations, two missense (p.Ser111Cys, p.Thr124Ala) and one frameshift (p.Tyr145fs) were found, and a molecular modelling approach was used to test the effects of these mutations on the protein structure. Electrostatic distribution changes within the protein, caused by the amino acid substitution, fit in with phenotypes presented by patients herein described. Our findings suggest that the clinical features associated with MPZ mutations depend partly on the nature of amino acid change and that molecular modelling may provide useful support, based on effects on secondary and tertiary protein structure, to predict the phenotype associated with MPZ mutations.
authors.affiliation: Department of Neuroscience, Ophthalmology and Genetics, University of Genoa, Genoa, Italy. pmandich@unige.it
authors.forename: Paola
authors.initials: P
authors.lastname: Mandich
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Simona
authors.initials: S
authors.lastname: Capponi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Geroldi
authors.forename: Massimo
authors.initials: M
authors.lastname: Acquaviva
authors.forename: Rossella
authors.initials: R
authors.lastname: Gulli
authors.forename: Paola
authors.initials: P
authors.lastname: Ciotti
authors.forename: Fiore
authors.initials: F
authors.lastname: Manganelli
authors.forename: Marina
authors.initials: M
authors.lastname: Grandis
authors.forename: Emilia
authors.initials: E
authors.lastname: Bellone
mesh_terms: D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D016368:Frameshift Mutation; D006801:Humans; D009154:Mutation; D020125:Mutation, Missense; D018993:Myelin P0 Protein; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000473:pathology
chemical_list: D018993:Myelin P0 Protein