Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies

摘要

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 thedisease (CMT2). The MPZ role in the pathogenesis of both demyelinating and axonal inheritedneuropathies was evaluated in the Italian population by screening a cohort of 214 patients with CMT1or CMT2. A MPZ mutation frequency of 7.9% in demyelinating cases and of 4.8% in axonal cases wasobserved. In the total cohort (264 patients), including those with mutations in other genes, a mutationfrequency of 5.8% (7/121) in demyelinating cases and 4.2% (6/143) in axonal cases was found. Threenovel MPZ mutations, two missense (p.Ser111Cys, p.Thr124Ala) and one frameshift (p.Tyr145fs) werefound, and a molecular modelling approach was used to test the effects of these mutations on the proteinstructure. Electrostatic distribution changes within the protein, caused by the amino acid substitution, fit inwith phenotypes presented by patients herein described. Our findings suggest that the clinical featuresassociated with MPZ mutations depend partly on the nature of amino acid change and that molecularmodelling may provide useful support, based on effects on secondary and tertiary protein structure, topredict the phenotype associated with MPZ mutations.