PMP22 Thr118Met is not a clinically relevant CMT1 marker

It is controversial if peripheral myelin protein 2 gene (PMP22) Thr118Met r epresents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disea se type 1 (CMT1 patients), it can act as a recessive CMT1 mutation. To shed further light on this variant and its diagnostic value we searched for car riers in 1018 individuals from the German general population, in 104 proban ds with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disor der, in 187 patients with the 1.5-Mb duplication, and in 22 patients with a CMT1 phenotype who did not have any detectable anomaly in the PMP22 gene. Using allele-specific PCR we identified 14 [allele frequency (AF)=0.007] in the German general population, one (AF=0.01) in the HNPP group and six (AF =0.016) and two (AF=0.05) carriers of the PMP22 Thr118Met mutation in the C MT1 groups with and without gene defect. Carriers from all groups showed ne rve conduction velocities which did not differ from typical values for thes e groups. We conclude that the hemizygous occurrence of the 118Met allele d oes not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitr o expression systems, it seems possible that this mutation, together with y et unidentified factors, predisposes to CMT1. Alternatively, previously rep orted disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case th is mutation is not a clinically relevant disease marker.