MPZ – Charcot-Marie-Tooth disease type 3 (Dejerine-Sottas syndrome)

Charcot-Marie-Tooth disease type 3 (MONDO:0007790), also known as Dejerine-Sottas syndrome (DSS), is a severe, early-onset demyelinating peripheral neuropathy characterized by hypotonia, distal muscle weakness, and areflexia. DSS typically presents in infancy with delayed motor milestones, significant nerve conduction slowing, and pronounced onion-bulb formation on biopsy. MPZ encodes Myelin Protein Zero (P0), the major structural and adhesion glycoprotein of peripheral myelin, and pathogenic MPZ variants disrupt myelin compaction.

Inheritance is autosomal dominant, most commonly due to de novo MPZ point mutations in the extracellular or transmembrane domains. Segregation has been observed in multiplex families (two affected sisters with c.499G>C (p.Gly167Arg) arising from maternal germline mosaicism [PMID:10399750]) alongside numerous sporadic cases with de novo missense and truncating alleles.

Case series and cohort studies have reported over 15 distinct pathogenic MPZ variants in more than 20 unrelated DSS patients ([PMID:7506095], [PMID:8664899], [PMID:9222756]). The variant spectrum includes missense substitutions (e.g., p.Ser63Phe), nonsense alleles, and frameshifts. A representative truncating allele is c.643C>T (p.Gln215Ter), identified de novo in a congenital hypomyelination case with distal weakness, hypotonia, and areflexia ([PMID:10319895]).

Functional studies demonstrate that MPZ mutations cause dominant-negative effects on P0 adhesion and trafficking. In CHO and Schwannoma cell assays, P0 mutants fail to mediate homophilic adhesion and are mislocalized intracellularly ([PMID:10586242]). Transgenic mice expressing the Ile106Leu mutation recapitulate severe dysmyelination with tomacula and conduction deficits, supporting a toxic gain-of-function mechanism ([PMID:15148307]).

No definitive reports contradict the MPZ–DSS association. The collective genetic and experimental data fulfill ClinGen Strong evidence criteria for causality. MPZ testing enables molecular diagnosis, prognostic counseling, and informed therapeutic development.

Key take-home: MPZ heterozygous dominant mutations cause DSS via dominant-negative disruption of P0 adhesion and trafficking, underpinning a robust diagnostic marker for early-onset demyelinating neuropathy.

References

• Nature Genetics • 1993 • De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III). PMID:7506095
• Annals of Neurology • 1999 • Congenital hypomyelination due to myelin protein zero Q215X mutation. PMID:10319895
• Annals of the New York Academy of Sciences • 1999 • Characterization of the effect on adhesion of different mutations in myelin P0 protein. PMID:10586242
• 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

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