The PMP22 gene and its related diseases

Abstract

Peripheral myelin protein-22 (PMP22) is primarily expressed in the compact myelin of the peripheral nervous system. Levels of PMP22 have to be tightly regulated since alterations of PMP22 levels by mutations of the PMP22 gene are responsible for >50 % of all patients with inherited peripheral neuropathies, including Charcot-Marie-Tooth type-1A (CMT1A) with trisomy of PMP22, hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of PMP22, and CMT1E with point mutations of PMP22. While overexpression and point-mutations of the PMP22 gene may produce gain-of-function phenotypes, deletion of PMP22 results in a loss-of-function phenotype that reveals the normal physiological functions of the PMP22 protein. In this article, we will review the basic genetics, biochemistry and molecular structure of PMP22, followed by discussion of the current understanding of pathogenic mechanisms involving in the inherited neuropathies with mutations in PMP22 gene.

Figure 1. PMP22 gene structure and predicted protein structure

A. A schematic representation of a human PMP22 gene consists of six exons. Exon-1a containing transcripts predominantly express in myelinating Schwann cells. Exon-1b containing transcripts express in non-neuronal cells. B. A schematic representation of human PMP22 protein topology shows extracellular, intracellular and transmembrane domains. A variety of mutations causal for CMT4E are marked at the amino acid sites where the mutations take place.

Figure 2. Pathological findings in CMT1A and HNPP

A. A sural nerve biopsy was performed in a 70-year-old man with CMT1A. A semithin preparation shows numerous onion bulbs scattered over the entire visual field (from Berciano et al, JNNP 2006; 77: 1169-1176 with permission). B. Photomicrograph of sural nerve biopsy-teased nerve fiber preparation from a 23-year-old woman with HNPP, showing areas of myelin thickening (tomaculum). C. Photomicrograph of sural nerve biopsy epoxy semithin preparation, transverse section (methyl blue), from the patient illustrates multiple myelinated fibers with excessively thick myelin (tomaculum). B&C are from Crum et al, Muscle & Nerve 2000; 23: 979-983 with permission.

Figure 3

Hypothetical mechanisms in CMT1A, HNPP and CMT1E.