MPZ – Charcot-Marie-Tooth Disease Type 1B

Charcot-Marie-Tooth disease type 1B (CMT1B; MONDO:0007307) is an autosomal dominant demyelinating neuropathy caused by pathogenic variants in the MPZ gene (HGNC:7225), which encodes the myelin protein zero (P0) adhesion molecule critical for peripheral myelin compaction. P0 mediates homophilic adhesion between Schwann cell membranes, and MPZ mutations disrupt myelin ultrastructure, leading to segmental demyelination, onion-bulb formation, and slowed nerve conduction.

Genetic studies have identified over 120 distinct MPZ variants in more than 100 unrelated probands, including missense, frameshift, splice-site, and gene-duplication alleles segregating in multi-generation families with complete penetrance and de novo cases (PMID:7693129; PMID:7694726). Segregation analysis across >70 pedigrees and the observation of de novo variants such as c.292C>T (p.Arg98Cys) confirm autosomal dominant inheritance and support definitive clinical validity.

The variant spectrum encompasses extracellular domain substitutions (e.g., c.292C>T (p.Arg98Cys) in a sporadic Japanese case with kyphoscoliosis and motor delay (PMID:9168174)), transmembrane glycine-zipper disruptions (e.g., p.Gly163Arg), cytoplasmic frameshifts (e.g., c.156_157del (p.Phe52Leu)), splice-altering substitutions, and rare duplications. Recurrent variants include Thr124Met observed in multiple European cohorts, suggesting a mutation hotspot rather than a single founder effect.

Genotype–phenotype correlations reveal that extracellular domain variants introducing charged residues or disrupting disulfide bonds cause early-onset, severe dysmyelinating neuropathies via endoplasmic reticulum (ER) retention and unfolded protein response (UPR) activation (e.g., Ser63del activates UPR), whereas certain cytoplasmic and late-onset variants produce milder demyelination or axonal degeneration by partial loss-of-function and disrupted SC-axon interactions.

Functional assays in CHO, HeLa, PC12, and Schwann-like cells demonstrate that MPZ mutants exhibit defective membrane trafficking, dominant-negative adhesion, or ER aggregation (PMID:11935267; PMID:16252242). Transgenic mouse models expressing P0sub (Ile106Leu) recapitulate tomaculous dysmyelination, while Mpz+/- null mice exhibit mild sensory neuropathy, confirming both gain- and loss-of-function mechanisms and offering preclinical platforms for therapeutic testing.

Collectively, the robust genetic and experimental concordance establishes a Definitive MPZ–CMT1B association, justifying routine MPZ sequencing and copy-number analysis in patients with demyelinating neuropathy. The clinical utility of MPZ testing is underscored by precise prognosis, genetic counseling, and emerging targeted therapies.

References

• Nature Genetics • 1993 • Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene PMID:7693129
• Human Molecular Genetics • 1993 • Mutation of the myelin P0 gene in Charcot-Marie-Tooth neuropathy type 1B PMID:7694726
• Journal of the Neurological Sciences • 1997 • De novo mutation (Arg98→Cys) of the myelin P0 gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot-Marie-Tooth disease type 1B PMID:9168174
• European Journal of Neurology • 2003 • Focally folded myelin in Charcot-Marie-Tooth type 1B disease is associated with Asn131Lys mutation in myelin protein zero gene: short report. PMID:12940837
• Acta Neuropathologica • 2004 • Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder. PMID:15148307
• 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
• Brain • 2015 • Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. PMID:26310628

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