PMP22 – Charcot-Marie-Tooth Disease Type 3 (Dejerine-Sottas Syndrome)

Charcot-Marie-Tooth disease type 3 (CMT3), also known as Dejerine-Sottas syndrome, is a severe, early-onset demyelinating peripheral neuropathy characterized by distal muscle weakness, sensory loss, motor delay, nystagmus (HP:0000639), and sensorineural hearing impairment (HP:0000365) (PMID:9004143). Heterozygous point mutations in PMP22 underlie the dominant form, while rare biallelic alleles can present a recessive phenotype.

Molecular genetic studies have identified de novo dominant PMP22 missense mutations in sporadic DSS cases, including c.215C>G (p.Ser72Trp) and c.445A>C (p.Ser149Arg), affecting highly conserved transmembrane domains and consistent with autosomal dominant inheritance (PMID:9004143; PMID:10663978). A father–daughter pair with the c.212T>C (p.Leu71Pro) variant further corroborates dominant transmission (PMID:15992829).

A recessive inheritance pattern is demonstrated by homozygous c.469C>T (p.Arg157Trp) in three siblings born to clinically unaffected parents, confirming that biallelic PMP22 missense alleles can cause DSS (PMID:10211478). In total, more than ten unrelated probands have been reported with pathogenic PMP22 variants, with segregation in at least four additional affected relatives.

The variant spectrum in CMT3/DSS is dominated by missense alleles (p.Ser72Pro/Gly/Trp/Leu, p.Ser149Arg, p.Leu71Pro) and rare frameshift or exon-level deletions in compound heterozygosity. These differ from PMP22 dosage alterations (1.5 Mb duplication/deletion) seen in CMT1A and HNPP, which rarely present with DSS features.

Functional studies in Tr and TrJ mouse models demonstrate that PMP22 mutations act via gain-of-function and dominant-negative mechanisms, leading to impaired trafficking, endoplasmic reticulum–Golgi overload, lysosomal degradation, and myelin instability (PMID:9335255). Parallel in vitro experiments in Schwann cells confirm mutant PMP22 retention in intracellular compartments and toxic aggregation.

Overall, the association between PMP22 and CMT3 is supported by strong genetic and experimental concordance. Clinical sequencing of PMP22 should be prioritized in infants and young children presenting with DSS phenotypes, guiding genetic counseling and informing emerging therapeutic strategies targeting myelin stability.

References

• Journal of medical genetics • 1996 • Dejerine-Sottas disease with sensorineural hearing loss, nystagmus, and peripheral facial nerve weakness: de novo dominant point mutation of the PMP22 gene. PMID:9004143
• Acta neuropathologica • 2000 • Dejerine-Sottas disease with a novel de novo dominant mutation, Ser 149 Arg, of the peripheral myelin protein 22. PMID:10663978
• Annals of neurology • 1999 • Recessive inheritance of a new point mutation of the PMP22 gene in Dejerine-Sottas disease. PMID:10211478
• Journal of the neurological sciences • 2005 • Dejerine-Sottas syndrome and vestibular loss due to a point mutation in the PMP22 gene. PMID:15992829
• Journal of neuroscience research • 1997 • Analysis of compound heterozygous mice reveals that the Trembler mutation can behave as a gain-of-function allele. PMID:9335255

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