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Clinical and pathological observations in men lacking the gap junction protein connexin 32
A F Hahn1, P J Ainsworth, C C Naus
1Department of Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, Canada. angelika.hahn@lhsc.on.ca
Abstract:
The X-linked form of Charcot-Marie-Tooth disease has been associated with mutations in the connexin 32 (Cx 32) gene, which encodes a gap junction protein. The majority of identified mutations are missense, but a few nonsense mutations or frame-shifting microdeletions have been encountered. Functional assessments of the mutated gap junction protein have demonstrated altered or simple losses of function. Mutations segregate with a typical clinical phenotype, which is the result of an age-related, progressive neuropathy. The mechanisms that cause the nerve damage are unknown. This report describes the consequences of a unique deletion mutation that eliminates the entire coding sequence of Cx 32, resulting in the absence of the Cx 32 gap junction protein in affected, hemizygous men. The clinical expression of this unique mutation was studied by the clinical, electrophysiological, and pathological evaluation of this kinship of five generations. The resulting severe neuropathy combines features of demyelination, notably in paranodal distribution, and distal accentuated axonal degeneration. The predicted absence of Cx 32 gap junctions is shown to be associated with a severe dysfunction of the axon-Schwann cell unit. Observed changes resemble those of Cx 32-null mice. No central nervous system changes were demonstrated.
Insights
A unique deletion mutation in the connexin 32 (Cx 32) gene causes X-linked Charcot-Marie-Tooth disease by eliminating Cx 32 protein. This absence leads to severe nerve damage, affecting the axon-Schwann cell unit.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- X-linked Charcot-Marie-Tooth disease is linked to connexin 32 (Cx 32) gene mutations.
- Most mutations are missense, causing altered or lost Cx 32 protein function.
- The exact mechanisms of nerve damage in Cx 32-related neuropathy remain unclear.
Purpose of the Study:
- To investigate the consequences of a complete Cx 32 gene deletion mutation.
- To evaluate the clinical, electrophysiological, and pathological effects of Cx 32 absence in a five-generation family.
Main Methods:
- Clinical evaluation of affected individuals.
- Electrophysiological studies of nerve function.
- Pathological examination of nerve tissue.
Main Results:
- A unique deletion mutation resulted in the complete absence of Cx 32 protein in hemizygous males.
- The resulting neuropathy exhibited demyelination (paranodal) and distal axonal degeneration.
- Absence of Cx 32 gap junctions correlated with severe axon-Schwann cell unit dysfunction.
- Observed pathology mimicked that of Cx 32-null mice, with no central nervous system involvement.
Conclusions:
- Complete absence of Cx 32 protein causes a severe neuropathy resembling X-linked Charcot-Marie-Tooth disease.
- The Cx 32 protein is crucial for maintaining the integrity and function of the axon-Schwann cell unit.
- This study provides insights into the pathogenesis of Cx 32-related neuropathies.
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