PMP22 Thr118Met is not a clinically relevant CMT1 marker

Abstract

It is controversial if peripheral myelin protein 22 gene (PMP22) Thr118Met represents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disease 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 carriers in 1018 individuals from the German general population, in 104 probands with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disorder, 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 CMT1 groups with and without gene defect. Carriers from all groups showed nerve conduction velocities which did not differ from typical values for these groups. We conclude that the hemizygous occurrence of the 118Met allele does not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitro expression systems, it seems possible that this mutation, together with yet unidentified factors, predisposes to CMT1. Alternatively, previously reported disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case this mutation is not a clinically relevant disease marker.

T118M Variant of PMP22 Gene Presents with Painful Peripheral Neuropathy and Varying Charcot-Marie-Tooth Features: A Case Series and Review of the Literature

“…However, the clinical relevance of the T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive [2], partial loss of function [8–10], or a benign variant [11]. In this study, we report three cases in support that the T118M variant of the PMP22 gene is a partial loss of function mutation rather than a benign variant.…”

“…However, other studies presented data in support of it being a deleterious variant. The largest study is a case-control study with 1018 healthy subjects, 104 unrelated patients with hereditary neuropathy with liability to pressure palsies (HNPP), and 187 patients with Charcot-Marie-Tooth disease type 1 (CMT1) [11]. It found T118M to be associated with CMT1A without the 1.5-Mb duplication (P=0.0429), but not associated with HNPP or CMT1 with the 1.5Mb duplication.…”

REPORT of a novel mutation in the PMP22 gene causing an axonal neuropathy

“…However, the other patients in that study, who carried a heterozygous T118M PMP22 mutation, developed HNPP 16. In other studies, the T118M substitution was found in 1.4% of healthy controls in a German population and 1.9% in a Swedish population, and thus it was unclear whether it was a benign polymorphism or a recessive CMT mutation 17, 18…”

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

“…Roa et al (2) interpreted it as a recessive condition, since a patient carrying a 17p11.2-p12 deletion in one chromosome and this point mutation in the other one expressed a severe CMT1 phenotype, while her younger son who carried only the Thr(118)Met allele was phenotypically normal, and her two older boys who inherited the deleted chromosome manifested a mild HNPP phenotype. A second similar pedigree was found (3) supporting this initial idea, that was questioned by the case described by Young et al (6), in which the hemizygous patient with the Thr(118)Met mutation did have the usual HNPP phenotype. Nelis et al (4) raised the possibility that this substitution could just be a polymorphism as they found an allele frequency of 0.019 in a study on 262 control individuals from the Swedish population.…”