Clinical features and molecular modelling of novel MPZ mutations in demyelinatin

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Eur J Hum Genet. 2009 Mar 18.

Clinical features and molecular modelling of novel MPZ mutations in

demyelinating and axonal neuropathies.

Mandich P, Fossa P, Capponi S, Geroldi A, Acquaviva M, Gulli R, Ciotti P,

Manganelli F, Grandis M, Bellone E.

1Department of Neuroscience, Ophthalmology and Genetics - Section of Medical

Genetics, University of Genoa, Viale Benedetto XV, Genoa, Italy.

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.