A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

Abstract

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy.

Myelin Fat Facts: An Overview of Lipids and Fatty Acid Metabolism

“…PMP2 has have high binding affinity to fatty acids and cholesterol [137,138] and is proposed to participate in fatty acid transport and fatty acid metabolism [133,139,140]. Interestingly, several PMP2 mutations were shown to cause a demyelinating form of Charcot-Marie-Tooth disease [141][142][143]; and upregulation of axonal neuregulin signaling causes an increase in PMP2 expression [144,145].…”

Recent advances in the genetic neuropathies

“…If one considers only autosomal dominant demyelinating CMT, almost all patients have mutations in one of the following genes; GJB1, PMP22, MPZ, EGR2, LITAF or NEFL [7,8]. Mutations in PMP2 can now be added to this list following the identification of three mutations in four families with autosomal dominant CMT1 that was indistinguishable from CMT1A [3,9,10]. PMP2 accounts for 5% of peripheral myelin proteins and both knockdown and overexpression of wild type PMP2 cause nerve conduction velocity slowing suggesting that like PMP22, PMP2 gene dosage is critical to peripheral nerve conduction [3,9,11].…”

Sub-atomic resolution crystal structures reveal conserved geometric outliers at functional sites

“…P2 has a role in maintaining lipid homeostasis in the developing nervous system [7]. Mutations in the gene encoding P2 are linked to Charcot-Marie-Tooth disease [8][9][10][11][12]. We have previously determined the atomic-resolution 0.93-Å structure of human P2 [13], providing accurate insights into its ligand-binding determinants.…”