title: Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease.
abstract: The X-linked form of Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32), a gap junction protein expressed by Schwann cells where it forms reflexive channels that allow the passage of ions and signaling molecules across the myelin sheath. Although most mutations result in loss of function, several studies have reported that some retain the ability to form homotypic intercellular channels. To gain insight into the molecular defect of three functional CMTX variants, S26L, Delta111-116 and R220stop, we have used several fluorescent tracers of different size and ionic charge to compare their permeation properties to those of wild-type Cx32. Although all mutations allowed the passage of the dye with the smallest molecular mass, they exhibited a clear reduction in the permeability of either one or all of the probes with respect to wild-type channels, as assessed by the percentage of injections showing dye coupling. These data reveal that a lower size cutoff distinguishes these functional CMTX variants from wild-type channels and suggest that this defect may be of pathophysiological relevance.
authors.affiliation: Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, University of Trieste, via Licio Giorgieri 1, 34127 Trieste, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bicego
authors.forename: Sabina
authors.initials: S
authors.lastname: Morassutto
authors.forename: Victor H
authors.initials: VH
authors.lastname: Hernandez
authors.forename: Marcello
authors.initials: M
authors.lastname: Morgutti
authors.forename: Fabio
authors.initials: F
authors.lastname: Mammano
authors.forename: Paola
authors.initials: P
authors.lastname: D'Andrea
authors.forename: Roberto
authors.initials: R
authors.lastname: Bruzzone
mesh_terms: D015153:Blotting, Western; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D018408:Patch-Clamp Techniques; D010539:Permeability; D014162:Transfection; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D007473:Ion Channels; D000097002:Gap Junction beta-1 Protein