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-MarieTooth 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.

Mutations associated with Charcot–Marie–Tooth disease cause SIMPLE protein mislocalization and degradation by the proteasome and aggresome–autophagy pathways

“…Protein misfolding and aggregation caused by genetic mutations or other factors has been shown to underlie the pathogenesis of many neurological diseases, including Parkinson disease and Alzheimer disease (Selkoe, 2004). Our findings that CMT1C mutations cause SIMPLE protein misfolding and aggregation, together with previous reports linking misfolded peripheral myelin protein 22 (PMP22) and myelin protein zero (MPZ) to other subtypes of demyelinating CMT (Shames et al, 2003;Myers et al, 2008;Mandich et al, 2009), suggest protein misfolding as a common cause of demyelinating peripheral neuropathies.…”

Two novel MPZ mutations in Chinese CMT patients

“…The MPZ mutation can cause demyelinating CMT (CMT1B), axonal CMT (CMT2I/2J), Dejerine‐Sottas neuropathy, or congenital hypomyelinating neuropathy (Dacci et al ., ) . Currently, more than 120 different MPZ mutations, both familial and sporadic, have been described (http://www.molgen.ua.ac.be/CMTMutations) (Mandich et al ., ) .…”

Protein misfolding and clearance in demyelinating peripheral neuropathies

“…[6][7][8] and MPZ. 9,10 How misfolding of these membrane proteins with different topologies contributes to demyelinating neuropathy remain unknown. We found that misfolded SIMPLE forms abnormal cytosolic aggregates and mediates erroneous interactions with cellular proteins, 3 which are pathogenic mechanisms characteristic of many protein-misfolding diseases.…”