Charcot‐Marie‐Tooth Neuropathy Type 2 And P0 Point Mutations: Two Novel Amino Acid Substitutions (ASP61GLY, TYR119CYS) and a Possible “Hotspot” on THR124MET

Abstract

Mutations in the gene for the major protein component of peripheral nerve myelin, myelin protein zero (MPZ, PO), cause hereditary disorders of Schwann cell myelin such as Charcot‐Marie‐Tooth neuropathy type 1B (CMT1B), Dejerine‐Sottas syndrome (DSS), and congenital hypomyelinating neuropathy (CHN). More recently, PO mutations were identified in the axonal type of CMT neuropathy, CMT2, which is different from the demyelinating variants with respect to electroneurography and nerve pathology. We screened 49 patients with a clinical and histopathological diagnosis of CMT2 for mutations in the PO gene. Three heterozygous single nucleotide changes were detected: two novel missense mutations, Asp61Gly and Tyr119Cys, and the known Thr124Met substitution, that has already been reported in several CMT patients from different European countries. Haplotype analysis for the PO locus proved that our patients with the 124Met allele were not related to a cohort of patients with the same mutation, all of Belgian descent and all found to share a common ancestor (7). Our data suggest that PO mutations account for a detectable proportion of CMT2 cases with virtually every patient harbouring a different mutation but recurrence of the Thr124Met amino acid substitution. The high frequency of this peculiar genotype in the European CMT population is presumably not only due to a founder effect but Thr124Met might constitute a mutation hotspot in the PO gene as well.