MPZ – Charcot–Marie–Tooth disease type 2J

MPZ (myelin protein zero) encodes the principal structural protein of peripheral nerve myelin and is implicated in a spectrum of hereditary neuropathies. Charcot–Marie–Tooth disease type 2J (CMT2J) is an autosomal dominant, late-onset, axonal neuropathy characterized by length-dependent sensorimotor deficits, often accompanied by pes cavus, hearing impairment, and tonic pupil phenomena (HP:0009830; HP:0001761; HP:0000365; HP:0012074).

Heterozygous p.Thr124Met (c.371C>T (p.Thr124Met)) in MPZ segregates with disease in a three-generation pedigree: a 56-year-old proband and her 29-year-old son presented with late-onset sensorimotor axonal neuropathy and pes cavus, whereas an unaffected daughter lacked neuropathy (PMID:19629567). A separate case report describes a 69-year-old woman with CMT2J carrying the identical variant and manifesting Adie’s pupil and deafness (PMID:26234237).

A founder effect for c.371C>T (p.Thr124Met) is supported by haplotype sharing across unrelated families from Belgium, Germany, Japan, Italy, North America, and Costa Rica, consistent with recurrent occurrence in at least five distinct pedigrees (PMID:25720167).

c.371C>T (p.Thr124Met) is the predominant recurrent mutation in CMT2J, with >10 unrelated probands documented. Heterozygous inheritance, clear segregation, and absence in healthy controls underpin robust genetic evidence for pathogenicity.

Functional studies of MPZ variants demonstrate that disease-associated missense and truncating mutations disrupt P0 trafficking, homophilic adhesion, and myelin compaction via dominant-negative mechanisms. In particular, cytoplasmic and extracellular domain mutants abolish adhesion in cell assays and induce endoplasmic reticulum retention with unfolded protein response activation (PMID:11673479; PMID:16252242).

Integration of genetic segregation, founder haplotype, and functional concordance supports a Strong ClinGen clinical validity classification for MPZ–CMT2J association. c.371C>T (p.Thr124Met) screening enables definitive diagnosis, familial risk assessment, and informs future therapeutic strategies targeting P0 folding and trafficking.

References

• Journal of neurology • 2009 • Charcot–Marie–Tooth disease type 2J with MPZ Thr124Met mutation: clinico-electrophysiological and MRI study of a fam PMID:19629567
• Internal medicine (Tokyo, Japan) • 2015 • Parasympathetic Dominant Autonomic Dysfunction in Charcot-Marie-Tooth Disease Type 2J with the MPZ Thr124Met Mutation PMID:26234237
• Revista de biologia tropical • 2014 • A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype PMID:25720167
• The Journal of cell biology • 2001 • Mutations in the cytoplasmic domain of P0 reveal a role for PKC-mediated phosphorylation in adhesion and myelination PMID:11673479
• American journal of human genetics • 2005 • Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants PMID:16252242

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