PMP2 – Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) disease is a common inherited peripheral neuropathy characterized by demyelination, slow nerve conduction velocities and distal muscle weakness. While classic CMT1A is caused by PMP22 duplication, variants in PMP2 (peripheral myelin protein 2) have emerged as a distinct autosomal dominant cause of demyelinating CMT (CMT1). Initial identification of the p.Ile43Asn mutation in a multigenerational family confirmed dominant inheritance, early onset in the first two decades, distal leg muscle atrophy and characteristic onion bulb formation in sural nerve biopsies (PMID:26828946). Subsequent cohort screening in five additional families revealed three clustered missense variants—p.Ile43Asn, p.Thr51Pro and p.Ile52Thr—in the helix–turn–helix region and two novel substitutions, p.Met114Thr and p.Val115Ala, affecting conserved lipid-binding residues (PMID:31412900).

All reported PMP2 variants segregate with disease in at least six unrelated families (PMID:31412900), supporting complete penetrance in heterozygotes and an autosomal dominant pattern. To date, seven distinct missense changes have been identified, clustering in two hotspots: residues 43–52 and 114–115. No loss-of-function or splice variants have been observed, consistent with a dominant toxic or gain-of-function mechanism. Population screening in 315 Chinese CMT probands found no additional PMP2 pathogenic alleles, indicating a rarity of PMP2-related CMT in that cohort (PMID:29336362).

Functional assays in transgenic mice demonstrate that overexpression of mutant (p.Ile43Asn) or even wild-type PMP2 leads to reduced motor nerve conduction velocities, shortened internodal lengths and demyelinating pathology, mirroring human CMT1 (PMID:26828946). Structural and biophysical studies of the I50del, M114T and V115A variants reveal near-native folds but reduced thermal stability and altered fatty acid binding, implying impaired lipid transport and membrane stacking functions (PMID:34138518).

Integration of genetic and experimental data indicates a gain-of-function or dominant-negative effect of PMP2 missense variants on myelin integrity. Seven probands across six families with segregating missense changes, consistent AD inheritance, and concordant animal and structural studies support a Strong gene–disease association. Further large-scale screening may uncover additional variants but is not required for current clinical utility.

Key Take-Home: Heterozygous missense variants in PMP2 cause autosomal dominant demyelinating CMT; inclusion of PMP2 in CMT gene panels aids diagnosis and family counseling.

References

• PLoS Genetics • 2016 • A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy PMID:26828946
• Orphanet Journal of Rare Diseases • 2019 • Peripheral myelin protein 2 - a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy PMID:31412900
• The FEBS Journal • 2021 • Human myelin protein P2: from crystallography to time-lapse membrane imaging and neuropathy-associated variants PMID:34138518

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