A novel point mutation in the peripheral myelin protein 22 (PMP22) gene associated with Charcot-Marie-Tooth disease type 1A

Abstract

Article abstract-We studied the peripheral myelin protein gene PMP-22 in a large Sardinian family with Charcot-Marie-Tooth disease type 1A (CMT1A), in which the duplication commonly found in CMT1A was absent, but with evidence of linkage on chromosome 17. Sequencing of DNA and cDNA showed a missense point mutation G³⁶⁸ [arrow right] T in exon 5 of PMP22, predicted to determine a valine for glycine substitution at codon 107, which could be ploted in the center of the PMP22 protein putative transmembrane domain III. Using sequence-specific oligonucleotide probes (SSOP), we found the point mutation in all affected CMT1A subjects but not in healthy family members or in 314 chromosomes of controls, thus indicating that the G³⁶⁸ [arrow right] T point mutation is not a polymorphism. In the hypothetical model of PMP22, the amino acid at position 107 plots deeply into alpha-helical transmembrane domain III, a domain where point mutations have never previously been found. Although the same mutation was present in all CMT1A subjects examined, clinical findings showed a different stereotyped pattern in relation to the generation examined, for a progressive increase in severity and an earlier onset from the first to the third generation examined. Molecular analysis suggests that CMT1A disease in this family is due to the G³⁶⁸ [arrow right] T point mutation, although other mechanisms may account for the clinical variability in the members of different generations.

NEUROLOGY 1997;48: 489-493