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Connexin32 and X-linked Charcot-Marie-Tooth disease

L J Bone1, S M Deschênes, R J Balice-Gordon

  • 1Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Neurobiology of Disease
|January 1, 1997
PubMed

Insights

Mutations in the connexin32 (Cx32) gene cause X-linked Charcot-Marie-Tooth disease by disrupting myelin. Some Cx32 mutations prevent protein transport or function, potentially damaging nerve cells and axons.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Charcot-Marie-Tooth disease (CMT) is a group of inherited neuropathies affecting peripheral nerves.
  • X-linked CMT is caused by mutations in the connexin32 (Cx32) gene, which encodes a gap junction protein.
  • Over 130 Cx32 mutations are known, impacting various parts of the Cx32 protein.

Purpose of the Study:

  • To investigate the functional consequences of Cx32 mutations in X-linked Charcot-Marie-Tooth disease.
  • To understand how different Cx32 mutations affect protein localization and gap junction formation.
  • To elucidate the role of Cx32 in myelinating Schwann cells and peripheral nerve integrity.

Main Methods:

  • Analysis of Cx32 protein localization and function in transfected cells.
  • Examination of Cx32 localization in peripheral nerve myelin.
  • Inference of Cx32's role in myelin sheath structure and function.

Main Results:

  • Mutant Cx32 proteins exhibit varied cellular localization, with some failing to reach the cell surface.
  • Only one characterized mutant Cx32 protein forms functional gap junctions.
  • Cx32 is localized to incisures and paranodes in peripheral nerve myelin.

Conclusions:

  • Cx32 mutations can impair gap junction function and/or protein trafficking, leading to neuropathy.
  • The localization of Cx32 suggests a role in forming "reflexive" gap junctions across the myelin sheath.
  • Cx32 mutations may injure myelinating Schwann cells by disrupting this short diffusion pathway, causing X-linked Charcot-Marie-Tooth disease.

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