Stoichiometric Alteration of PMP22 Protein Determines the Phenotype of Hereditary Neuropathy With Liability to Pressure Palsies

Abstract

Background: Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by a 1.4-megabase deletion at chromosome 17p11.2, which bears the PMP22 gene and other genes. However, whether other genes besides PMP22 contribute to the phenotype is unknown. Whether any mutation within the coding region of the PMP22 gene ultimately causes HNPP by reducing the amount of peripheral myelin protein 22 (PMP22) expressed in myelin is also unknown.Objective: To determine whether affected patients develop a phenotype identical to that found in HNPP and whether the leucine 7 frameshift (Leu7fs) mutation reduces PMP22 levels in myelin. Design:We evaluated affected family members by neurological examination, electrophysiology, and skin biopsies. We identified a large family with a Leu7fs mutation of PMP22 (11 affected members across 3 generations) that predicts truncation of the protein prema-turely and eliminates PMP22 expression from the mutant allele.Results: We found that PMP22 levels were reduced in peripheral nerve myelin in dermal skin biopsies in patients with an Leu7fs mutation. Through clinical and electrophysiological evaluation, we also found that patients with the Leu7fs mutation were indistinguishable from patients with HNPP caused by deletion. We also found that a lengthdependent axonal loss became pronounced in elderly patients with Leu7fs mutations, similar to what has been described in heterozygous knockout mice (pmp22+/−).Conclusions: Taken together, these results confirm that the phenotypic expression is identical in patients with Leu7fs mutation and patients with HNPP caused by chromosome 17p11.2 deletion. They also demonstrate that reduction of PMP22 is sufficient to cause the full HNPP phenotype.

Distinctive patterns of sonographic nerve enlargement in Charcot–Marie–Tooth type 1A and hereditary neuropathy with pressure palsies

“…In HNPP this results in prolongation of the distal motor latencies and conduction slowing at typical sites susceptible to mechanical compression ( Fig. 4) (Gouider et al, 1995;Li et al, 2007). Our study demonstrated enlargement of nerves and fascicles restricted to sites of entrapment HNPP (Fig.…”

“…4) (Madrid and Bradley, 1975;Gouider et al, 1995;Gabreels-Festen and Wetering, 1999;Keller and Chance, 1999;Sander et al, 2000;Shy et al, 2002;Li et al, 2007Li et al, , 2013. In HNPP this results in prolongation of the distal motor latencies and conduction slowing at typical sites susceptible to mechanical compression ( Fig.…”

Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP

“…PMP22 encodes a tetra-span membrane protein primarily expressed in peripheral nerve myelin [6–8]. Mice with heterozygous knockout of Pmp22 recapitulate the pathology of humans with HNPP, including tomacula with excessive myelin decompaction that extends from paranodes to juxtaparanodes and internodes [9].…”

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

“…These include Leu4Ter,9 Leu7 fs,10, 11 Gly94 fs,12, 23 Tyr97 fs,24 and Thr99 fs25 PMP22 . Mutations that cause an HNPP phenotype eliminate the mutant allele by processes such as nonsense‐mediated decay 11, 26. Thus, these are complete loss‐of‐function alleles similar to traditional HNPP in which the PMP22 allele is deleted 13.…”

“…Most CMT1E mutations are missense mutations probably resulting in a gain‐of‐new protein function 8. In contrast, some PMP22 point mutations produce a loss‐of‐protein function by a shift in the protein reading frame, leading to premature termination of translation 9, 10, 11, 12. A similar loss of function can also be caused by the reciprocal deletion of PMP22 within 17p12 that caused the CMT1A duplication.…”