Pathogenesis of X-Linked Charcot-Marie-Tooth Disease: Differential Effects of Two Mutations in Connexin 32

Charles K. Abrams, Mona Freidin, Feliksas Bukauskas, Kostantin Dobrenis, Thaddeus A. Bargiello, Vytautas Verselis, Michael V. L. Bennett, Lei Chen, Zarife Sahenk

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Abstract

X-Linked Charcot-Marie-Tooth disease is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding connexin 32 (Cx32). Cx32 is expressed at the paranodes and Schmidt-Lantermann incisures of myelinating Schwann cells in which it is believed to form a reflexive pathway between the abaxonal and adaxonal cytoplasmic domains. Patients with the Val181Ala (V181A) mutation have a severe peripheral neuropathy. Experiments using a nude mouse xenograft system show that Schwann cells expressing only this mutant form of Cx32 are profoundly impaired in their ability to support the earliest stages of regeneration of myelinated fibers. Coupling between paired Xenopus oocytes expressing V181A is reduced compared with the coupling between oocytes expressing wild-type human Cx32 (32WT), and protein levels assayed by Western blot are substantially lower. Immunocytochemisty shows that Neuro2a cells expressing the V181A mutant have very few gap junction plaques compared with cells expressing 32WT; Cx32 protein levels are lower in these cells than in those expressing 32WT. Because failure of normal regeneration is evident before formation of myelin, loss of function of Cx32 may impact on the function of precursors of the myelinating Schwann cell before the formation of the hypothesized reflexive pathway. The Glu102Gly (E102G) mutation leads to a milder phenotype. Early regeneration is normal in grafts with Schwann cells expressing the E102G mutant. The only abnormality detected in the behavior of its channel is increased sensitivity to acidification-induced closure, a property that may lead to reduced gap junction coupling during periods of metabolic stress. This restricted functional abnormality may explain the relatively mild phenotype seen in the xenograft model and in E102G patients.

Original languageEnglish (US)
Pages (from-to)10548-10558
Number of pages11
JournalJournal of Neuroscience
Volume23
Issue number33
StatePublished - Nov 19 2003

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Charcot-Marie-Tooth Disease
Schwann Cells
Mutation
Regeneration
Gap Junctions
Heterografts
Oocytes
Phenotype
Physiological Stress
Aptitude
Peripheral Nervous System Diseases
Myelin Sheath
Xenopus
Nude Mice
connexin 32
Western Blotting
Transplants
Genes
Proteins

Keywords

  • Charcot-Marie-Tooth disease
  • Connexin 32
  • Myelin regeneration
  • Peripheral neuropathy
  • Xenograft myelin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Abrams, C. K., Freidin, M., Bukauskas, F., Dobrenis, K., Bargiello, T. A., Verselis, V., ... Sahenk, Z. (2003). Pathogenesis of X-Linked Charcot-Marie-Tooth Disease: Differential Effects of Two Mutations in Connexin 32. Journal of Neuroscience, 23(33), 10548-10558.

Pathogenesis of X-Linked Charcot-Marie-Tooth Disease : Differential Effects of Two Mutations in Connexin 32. / Abrams, Charles K.; Freidin, Mona; Bukauskas, Feliksas; Dobrenis, Kostantin; Bargiello, Thaddeus A.; Verselis, Vytautas; Bennett, Michael V. L.; Chen, Lei; Sahenk, Zarife.

In: Journal of Neuroscience, Vol. 23, No. 33, 19.11.2003, p. 10548-10558.

Research output: Contribution to journalArticle

Abrams, CK, Freidin, M, Bukauskas, F, Dobrenis, K, Bargiello, TA, Verselis, V, Bennett, MVL, Chen, L & Sahenk, Z 2003, 'Pathogenesis of X-Linked Charcot-Marie-Tooth Disease: Differential Effects of Two Mutations in Connexin 32', Journal of Neuroscience, vol. 23, no. 33, pp. 10548-10558.
Abrams, Charles K. ; Freidin, Mona ; Bukauskas, Feliksas ; Dobrenis, Kostantin ; Bargiello, Thaddeus A. ; Verselis, Vytautas ; Bennett, Michael V. L. ; Chen, Lei ; Sahenk, Zarife. / Pathogenesis of X-Linked Charcot-Marie-Tooth Disease : Differential Effects of Two Mutations in Connexin 32. In: Journal of Neuroscience. 2003 ; Vol. 23, No. 33. pp. 10548-10558.
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abstract = "X-Linked Charcot-Marie-Tooth disease is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding connexin 32 (Cx32). Cx32 is expressed at the paranodes and Schmidt-Lantermann incisures of myelinating Schwann cells in which it is believed to form a reflexive pathway between the abaxonal and adaxonal cytoplasmic domains. Patients with the Val181Ala (V181A) mutation have a severe peripheral neuropathy. Experiments using a nude mouse xenograft system show that Schwann cells expressing only this mutant form of Cx32 are profoundly impaired in their ability to support the earliest stages of regeneration of myelinated fibers. Coupling between paired Xenopus oocytes expressing V181A is reduced compared with the coupling between oocytes expressing wild-type human Cx32 (32WT), and protein levels assayed by Western blot are substantially lower. Immunocytochemisty shows that Neuro2a cells expressing the V181A mutant have very few gap junction plaques compared with cells expressing 32WT; Cx32 protein levels are lower in these cells than in those expressing 32WT. Because failure of normal regeneration is evident before formation of myelin, loss of function of Cx32 may impact on the function of precursors of the myelinating Schwann cell before the formation of the hypothesized reflexive pathway. The Glu102Gly (E102G) mutation leads to a milder phenotype. Early regeneration is normal in grafts with Schwann cells expressing the E102G mutant. The only abnormality detected in the behavior of its channel is increased sensitivity to acidification-induced closure, a property that may lead to reduced gap junction coupling during periods of metabolic stress. This restricted functional abnormality may explain the relatively mild phenotype seen in the xenograft model and in E102G patients.",
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