MPZ – Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) comprises a group of inherited peripheral neuropathies characterized by progressive distal muscle weakness, sensory loss, and demyelination. The major myelin protein zero (P0), encoded by MPZ (HGNC:7225), is essential for compaction of peripheral nerve myelin sheaths. Mutations in MPZ disrupt myelin integrity and underlie both demyelinating (CMT1B) and axonal (CMT2) forms of CMT, accounting for approximately 5% of CMT cases.

MPZ-related CMT exhibits an autosomal dominant inheritance pattern, with numerous missense, nonsense, frameshift, splice, and duplication variants reported. A recurrent extracellular domain variant, c.389A>G (p.Lys130Arg), has been identified in 13 affected members of a Chinese pedigree, all demonstrating variable onset and severity (PMID:35174662). Other extracellular mutations, such as c.371C>T (p.Thr124Met), segregate with both demyelinating and axonal features in four symptomatic relatives within a Japanese family (PMID:12911457). Overall, at least 17 probands across multiple pedigrees harbor pathogenic MPZ variants, supporting robust genetic evidence.

Segregation analysis in kindreds with MPZ mutations confirms co-segregation with disease in extended families. The c.389A>G (p.Lys130Arg) variant shows complete concordance in 13 affected individuals (PMID:35174662), and Thr124Met segregates with phenotype in four additional family members (PMID:12911457). These findings underscore the autosomal dominant transmission and penetrance of MPZ mutations in CMT.

Functional studies demonstrate that CMT-associated MPZ mutants impair P0 adhesive function and intracellular trafficking. Mutations in the cytoplasmic PKC phosphorylation motif abolish P0-mediated adhesion and induce ER retention, triggering apoptosis in Schwann-like cells (PMID:11673479). In vivo, transgenic mice expressing the pathogenic Ile106Leu P0 mutation recapitulate tomaculous dysmyelination and reduced nerve conduction velocities, confirming a dominant-negative gain-of-function mechanism (PMID:15148307).

No significant conflicting evidence has been reported; functional and genetic data consistently link MPZ variants with peripheral neuropathy. Alternative phenotypes such as congenital hypomyelinating neuropathy and Dejerine-Sottas syndrome reflect allelic severity rather than refuting the CMT association.

In summary, MPZ mutations cause autosomal dominant Charcot-Marie-Tooth disease through dominant-negative disruption of P0 adhesion and myelin maintenance, with strong genetic segregation and concordant functional models. MPZ genetic testing informs diagnosis, family counseling, and targeted therapeutic development.

Key Take-home: MPZ-related CMT is a definitively established autosomal dominant neuropathy, where pathogenic P0 variants compromise myelin structure and function, guiding precise genetic diagnosis and potential intervention.

References

• Journal of the neurological sciences • 1997 • Tomaculous neuropathy in Charcot-Marie-Tooth disease with myelin protein zero gene mutation. PMID:9455987
• Acta neurologica Scandinavica • 2003 • Axonal and demyelinating forms of the MPZ Thr124Met mutation. PMID:12911457
• 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
• The Journal of cell biology • 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
• Molecular genetics & genomic medicine • 2022 • MPZ gene variant site in Chinese patients with Charcot-Marie-Tooth disease. PMID:35174662

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