PMP22 – Charcot-Marie-Tooth Disease Type 1A

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common autosomal dominant demyelinating peripheral neuropathy characterized by slowly progressive distal muscle weakness and sensory loss. The prototypical molecular etiology is a tandem 1.5-Mb duplication on chromosome 17p11.2-p12 encompassing the peripheral myelin protein 22 gene (PMP22), leading to PMP22 overexpression and myelin instability. Rare point mutations in PMP22 also underlie CMT1A and related phenotypes, demonstrating dosage sensitivity and varied inheritance modes (PMID:8252046).

Genetic evidence for PMP22 duplication in CMT1A includes over 1,000 unrelated patients confirmed by quantitative PCR or Southern blot, with uniform duplication breakpoints and autosomal dominant segregation in multiple pedigrees (PMID:9521270). Segregation analysis in 17 of 24 biopsy-confirmed patients showed concordant PMP22 copy number increase and CMT1A phenotype (PMID:15703022). Functional point mutations, such as c.353C>T (p.Thr118Met), c.47T>C (p.Leu16Pro), and c.215C>T (p.Ser72Leu), contribute to CMT1E or overlap syndromes, expanding the allelic spectrum and confirming a dominant-negative or gain-of-function mechanism.

The variant spectrum comprises large duplications, small indels, splice-site alterations, and missense mutations. For instance, c.353C>T (p.Thr118Met) has been identified in compound heterozygotes and heterozygotes, demonstrating both recessive and dominant effects (PMID:8252046). Other recurrent missense changes in transmembrane domains, such as c.47T>C (p.Leu16Pro), disrupt PMP22 folding and trafficking, and have been observed in multiple families with severe demyelinating phenotypes.

Functional and experimental data support aberrant intracellular trafficking and dosage-dependent pathogenicity. Transgenic and knockout mouse models (Tr, TrJ alleles) reveal that increased PMP22 dosage or point mutations induce hypomyelination, onion bulb formations, and Schwann cell stress responses (PMID:9335255). In vitro studies demonstrate that mutant PMP22 accumulates within endoplasmic reticulum–Golgi compartments, triggers lysosomal degradation pathways, and sequesters wild-type protein via heterodimerization (PMID:10078969). These concordant findings substantiate haploinsufficiency and toxic gain-of-function models.

Conflicting evidence exists regarding the pathogenicity of Thr118Met. Population screening revealed this variant at low frequency among controls without CMT1A features, suggesting it may act as a partial loss-of-function modifier rather than a fully penetrant mutation (PMID:11081809). Nevertheless, functional assays indicate that Thr118Met impairs PMP22 function under specific genetic backgrounds.

Integration of genetic and functional evidence yields a definitive gene-disease relationship under ClinGen criteria. Dosage testing by quantitative PCR and MLPA remains the diagnostic gold standard, while point mutation screens are indicated in patients lacking duplication. Understanding the dosage-sensitive threshold of PMP22 has informed experimental therapies aimed at modulating PMP22 expression. Key take-home: PMP22 copy number analysis is essential for accurate CMT1A diagnosis and genetic counseling.

References

• Neurology • 1998 • PCR-based strategy for the diagnosis of hereditary neuropathy with liability to pressure palsies and Charcot-Marie-Tooth disease type 1A PMID:9521270
• Journal of the peripheral nervous system • 2005 • Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients PMID:15703022
• 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
• Neurobiology of disease • 1999 • Impaired intracellular trafficking is a common disease mechanism of PMP22 point mutations in peripheral neuropathies PMID:10078969
• Journal of neurology • 2000 • PMP22 Thr118Met is not a clinically relevant CMT1 marker PMID:11081809
• Nature genetics • 1993 • Evidence for a recessive PMP22 point mutation in Charcot-Marie-Tooth disease type 1A PMID:8252046

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