MPZ mutation G123S characterization: evidence for a complex pathogenesis in CMT disease

Area of Science:

• Neurogenetics
• Molecular Biology
• Cell Biology

Background:

• Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies.
• CMT type 1B is often caused by mutations in the MPZ gene, which encodes the myelin protein zero (P(0)).
• Understanding novel mutations is crucial for diagnosing and potentially treating CMT.

Purpose of the Study:

• To investigate the clinical and cellular effects of a newly identified MPZ mutation in a Chinese family with CMT type 1B.
• To elucidate the molecular mechanisms underlying the disease phenotype caused by this mutation.

Main Methods:

• Clinical, electrophysiological, pathological, and genetic evaluations of affected family members.
• In vitro expression of wild-type and mutant P(0) proteins fused with fluorescent markers to track intracellular trafficking.
• Cell adhesion assays to assess the functional impact of the mutant P(0) protein.

Main Results:

• A novel MPZ mutation (c.367G>A) was identified, leading to a late-onset, demyelinating CMT phenotype with autosomal dominant inheritance.
• Patients exhibited significantly reduced median motor nerve conduction velocities (15.7-19.6 m/s).
• Neuropathology revealed severe myelinated fiber loss, onion bulb formation, and regenerative fiber clusters. Mutant P(0) protein showed aberrant retention in the endoplasmic reticulum and Golgi apparatus, and impaired cell adhesion.

Conclusions:

• The P(0)G123S mutation is linked to typical electrophysiological and pathological findings of late-onset demyelinating polyneuropathy.
• Aberrant intracellular trafficking of the mutant P(0) protein likely underlies the disease pathogenesis.
• Compromised cell adhesion due to the mutation contributes to the observed neuropathy.