Peripheral Myelin Protein-22 and Its Prominence in Charcot-Marie-Tooth Disease

Abstract

Charcot-Marie-Tooth disease (CMT) is an often-debilitating peripheral neuropathy that is a top-10 most prevalent human genetic disorder. However, there is currently no effective treatment. Over half of diagnosed CMT cases in western populations are caused by genetic variations that alter the expression levels or sequence of peripheral myelin protein 22 (PMP22). PMP22 is a tetraspan membrane glycoprotein that is most highly expressed in Schwann cells (SCs) of the peripheral nervous system (PNS) under conditions of myelination, where it plays multiple important roles. These functions are reduced in humans with only a single PMP22 allele, resulting in a common and usually mild form of CMT, hereditary neuropathy with liability to pressure palsies (HNPP). The rare type 1E CMT (CMT1E) is caused by amino acid variations in PMP22. The most common form of CMT (CMT1A) is caused by a third wild type (WT) allele of PMP22. The disease mechanisms of CMT1A are still incompletely understood, but there is much evidence that a major driver is proteostasis stress caused by WT PMP22 overexpression upon induction of myelination in SCs, possibly compounded by gain-of-function effects. Here, we explore PMP22’s structure, functions, trafficking, role in CMT, and prospects for successful therapeutic intervention.