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Updated: May 30, 2026

Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons
07:43

Modeling Charcot-Marie-Tooth Disease In Vitro by Transfecting Mouse Primary Motoneurons

Published on: January 7, 2019

Structural basis for the Trembler-J phenotype of Charcot-Marie-Tooth disease

Masayoshi Sakakura1, Arina Hadziselimovic, Zhen Wang

  • 1Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-8725, USA.

Structure (London, England : 1993)
|August 11, 2011
PubMed

Insights

The Leu16Pro mutation in peripheral myelin protein 22 (PMP22) causes Trembler-J disease by disrupting protein structure. This structural defect leads to misfolding, loss of function, and toxic aggregate accumulation, resulting in Charcot-Marie-Tooth disease.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • Mutations in peripheral myelin protein 22 (PMP22) are a common cause of Charcot-Marie-Tooth disease (CMTD).
  • The Leu16Pro mutation in PMP22 leads to the Trembler-J (TrJ) disease phenotype due to protein misassembly.

Purpose of the Study:

  • To elucidate the structural defects in partially folded TrJ PMP22 that promote Charcot-Marie-Tooth disease (CMTD)-causing misfolding.
  • To understand how the Leu16Pro mutation impacts PMP22 structure and function.

Main Methods:

  • Analysis of the structural defects in a partially folded state of TrJ PMP22.
  • Investigating the dynamics and tertiary interactions of transmembrane helix 1 (TM1) in the mutated protein.

Main Results:

  • Transmembrane helices 2-4 (TM2-4) form a molten globular bundle, while TM1 is dissociated in the partially folded state.
  • The TrJ mutation significantly disrupts TM1, increasing its dynamics and altering interactions with the TM2-4 core.
  • Mutated TM1 shows enhanced dissociation, leading to recognition by protein-folding quality control.

Conclusions:

  • The Leu16Pro mutation in PMP22 causes Charcot-Marie-Tooth disease by inducing structural defects that lead to protein misfolding.
  • Disruption of TM1 and its subsequent sequestration by quality control mechanisms result in PMP22 loss of function and toxic aggregate formation.

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