PMP22 – Charcot-Marie-Tooth disease type 1E

Charcot-Marie-Tooth disease type 1E (CMT1E) is an autosomal dominant demyelinating neuropathy caused by point and small in-frame deletion mutations in the peripheral myelin protein 22 gene (PMP22). Three unrelated probands have been reported: one de novo missense variant c.53T>G (p.Leu18Arg) in the first transmembrane domain resulting in early-onset severe neuropathy with pes planus, scoliosis and distal sensory loss (PMID:23313019), and two siblings with an in-frame deletion of exon 4 leading to endoplasmic reticulum retention of PMP22 and gain-of-function effects (PMID:28382305). Segregation analysis demonstrates two affected relatives within one family.

Functional studies across cellular and animal models reveal that CMT1E-associated PMP22 mutants (including exon 4 deletion and point mutants such as p.Leu16Pro and p.Gly150Arg/Asp) are misfolded, retained in the ER/intermediate compartment, form cytoplasmic aggregates and disrupt normal Schwann cell myelination. The Trembler-J mouse recapitulates key pathological features of human CMT1E, supporting a toxic gain-of-function mechanism.

References

• Neuromuscular disorders : NMD • 2013 • Biopsy in a patient with PMP22 exon 2 mutation recapitulates pathology of Trembler-J mouse. PMID:23313019
  
• Annals of clinical and translational neurology • 2017 • PMP22 exon 4 deletion causes ER retention of PMP22 and a gain-of-function allele in CMT1E. PMID:28382305

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