Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication

Abstract

The Thr(118)Met substitution in the peripheral myelin protein 22 (PMP22) gene has been detected in a number of families with demyelinating Charcot-Marie-Tooth (CMT1) neuropathy or with the hereditary neuropathy with liability to pressure palsy, but in none of them has it consistently segregated with the peripheral neuropathy. We describe here a CMT1 family (a 63-year-old man, his brother and his niece) in which two mutations on different chromosomes were found in the PMP22 gene, the 17p duplication, detected by fluorescent semiquantitative polymerase chain reaction (PCR) of microsatellite markers localized within the duplicated region on chromosome 17p11.2-p12, and the Thr(118)Met substitution, detected by direct sequencing the four coding exons of the PMP22 gene. A genotype/phenotype correlation study showed that the neuropathy segregates with the duplication and that the amino acid substitution does not seem to modify the clinical characteristics or the severity of the peripheral neuropathy. We did not find any evidence to characterize this substitution as a polymorphism in the population studied and we propose that the high frequency reported for this point mutation in the literature suggests that the Thr(118)Met substitution may be a hotspot for mutations in the PMP22 gene.

T118M PMP22 mutation causes partial loss of function and HNPP‐like neuropathy

“…Subsequently, several investigators identified the T118M mutation in unaffected parents of neuropathy patients 20 -23 or in compound heterozygotes whose phenotype was not dis-tinct from either HNPP or CMT1A. The T118M mutation has also been reported in a family in which the parents have a mild phenotype and carry both a CMT1A duplication and a T118M mutation, whereas a younger family member has a more severe disease but carries only the duplication, 24 suggesting that T118M is partial loss-of-function mutation that can mitigate the effects of the duplication.…”

Rough set‐based proteochemometrics modeling of G‐protein‐coupled receptor‐ligand interactions

“…Subsequently, several investigators identified the T118M mutation in unaffected parents of neuropathy patients20–23 or in compound heterozygotes whose phenotype was not distinct from either HNPP or CMT1A. The T118M mutation has also been reported in a family in which the parents have a mild phenotype and carry both a CMT1A duplication and a T118M mutation, whereas a younger family member has a more severe disease but carries only the duplication,24 suggesting that T118M is partial loss‐of‐function mutation that can mitigate the effects of the duplication.…”