title: Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations.
abstract: CMT1X, an X-linked inherited neuropathy, is caused by mutations in GJB1, which codes for Cx32, a gap junction protein expressed by Schwann cells and oligodendrocytes. Many GJB1 mutations cause central nervous system (CNS) abnormality in males, including stable subclinical signs and, less often, short-duration episodes characterized by motor difficulties and altered consciousness. However, some mutations have no apparent CNS effects. What distinguishes mutations with and without CNS manifestations has been unclear. Here we studied a total of 14 Cx32 mutations, 10 of which are associated with florid episodic CNS clinical syndromes in addition to peripheral neuropathy. The other 4 mutations exhibit neuropathy without clinical or subclinical CNS abnormalities. These "PNS-only" mutations (Y151C, V181M, R183C and L239I) form gap junction plaques and produce levels of junctional coupling similar to those for wild-type Cx32. In contrast, mutants with CNS manifestations (F51L, E102del, V139M, R142Q, R142W, R164W T55I, R164Q and C168Y) either form no morphological gap junction plaques or, if they do, produce little or no detectable junctional coupling. Thus, PNS and CNS abnormalities may involve different aspects of connexin function.
authors.affiliation: Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago IL, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Abrams
authors.affiliation: Department of Neurology, SUNY Downstate, Brooklyn, NY, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Goman
authors.affiliation: Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
authors.affiliation: Neurology Clinics and Neuroscience Laboratory, Cyprus Institute for Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Kleopas A
authors.initials: KA
authors.lastname: Kleopa
authors.affiliation: Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago IL, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Peinado
authors.affiliation: Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, Chicago IL, USA.
authors.forename: Mona M
authors.initials: MM
authors.lastname: Freidin
mesh_terms: D002450:Cell Communication; D002460:Cell Line; D002490:Central Nervous System / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000473:pathology*; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017933:Peripheral Nervous System / Q000473:pathology; D014162:Transfection; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D050505:Mutant Proteins; D000097002:Gap Junction beta-1 Protein