Why PMP22 Duplication Causes Myelin Degeneration in CMT1A
PMP22 duplication causes myelin degeneration through a gene dosage mechanism where three copies of the normal PMP22 gene lead to protein overexpression that overwhelms Schwann cell quality control systems, resulting in PMP22 protein misfolding, aggregation, and impaired trafficking to the myelin sheath, ultimately destabilizing myelin structure and causing progressive demyelination. 1, 2, 3
The Gene Dosage Mechanism
- CMT1A results from a 1.5-Mb tandem duplication on chromosome 17p11.2-p12 that encompasses the PMP22 gene, giving patients three copies of a completely normal gene rather than a mutant version 1, 4
- This represents the first autosomal dominant disease caused by gene dosage effect from an inherited DNA rearrangement, not from a defective protein 4
- The disease phenotype arises specifically from having three copies of the normal PMP22 gene, which causes overexpression of PMP22 mRNA and protein in Schwann cells 1, 2
Protein Overexpression and Cellular Dysfunction
- Overexpression of wild-type PMP22 protein overwhelms the endoplasmic reticulum quality control system in Schwann cells, leading to disproportionate increases in protein misfolding and mistrafficking 2, 3
- Single-cell flow cytometry studies demonstrate that as PMP22 expression increases, intracellular PMP22 accumulates to a greater extent than surface-trafficked protein, indicating progressive trafficking failure with higher expression levels 3
- PMP22 aggregates form in both rodent models overexpressing PMP22 and in dermal fibroblasts from CMT1A patients, suggesting cytotoxic aggregate formation contributes to disease pathology 3
Myelin Destabilization and Demyelination
- The accumulated misfolded PMP22 protein destabilizes the myelin sheath structure, as PMP22 normally plays a critical role in myelin formation and maintenance in peripheral nerves 1, 2
- Demyelination occurs as the primary pathological process, manifesting as slowed nerve conduction velocities on electrodiagnostic testing 5, 1
- Secondary axonal loss follows the demyelination, ultimately leading to progressive disability 2
Clinical-Pathological Correlation
- The length-dependent nature of axonal loss explains the characteristic distal muscle weakness and "stork leg" appearance in CMT1A patients 1
- Progressive demyelination results in the characteristic electrophysiological findings of markedly slowed nerve conduction velocities that define CMT1 as a demyelinating neuropathy 5, 6
Evidence from Therapeutic Studies
- Gene therapy studies using AAV9-delivered artificial miRNAs to reduce PMP22 expression in CMT1A mouse models demonstrate that normalizing PMP22 levels rescues the disease phenotype, improving nerve conduction velocities and ameliorating myelin pathology 2
- This therapeutic proof-of-concept confirms that excessive PMP22 expression is the direct cause of myelin degeneration, as reducing PMP22 to normal levels reverses the pathology 2, 4
Important Caveats
- While the gene dosage hypothesis is well-established, PMP22 mRNA expression in CMT1A patient nerve biopsies is not uniform—some patients show elevated levels while others have normal mRNA levels, though PMP22 protein is consistently reduced in all patients 7
- The highest PMP22 mRNA level was paradoxically found in the least affected patient in one study, suggesting the relationship between expression levels and disease severity may be more complex than simple overexpression 7
- Point mutations in PMP22 (accounting for 2.5% of CMT cases) can also cause CMT1A with similar phenotypes, indicating that both overexpression and structural protein abnormalities can disrupt myelin function 8, 9