Changes in permeability caused by connexin 32 mutations underlie X-linked Charcot-Marie-Tooth disease.
The relationship between the loss of connexin 32 function and clinical manifestations of X-linked Charcot-Marie-Tooth (CMTX) disease is unknown. Here, we report that eight of nine CMTX mutations investigated form channels with measurable electrical conductance. Single-channel studies of two mutations demonstrate reduced junctional permeability caused by a decrease in either pore size (S26L) or open channel probability (M34T) that favors residency in a low-conductance substate. Permeation of second messengers such as cAMP through reflexive gap junctions between adjacent cytoplasmic loops of myelinating Schwann cells is likely to be reduced or absent in these channels. We propose that CMTX mutations impair the transduction of signals arising from normal glial-neuronal interactions and thereby cause demyelination and axonal degeneration.
Oh
S
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Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ri
Y
Y
Bennett
M V
MV
Trexler
E B
EB
Verselis
V K
VK
Bargiello
T A
TA
D000818:Animals; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D017630:Connexins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D004553:Electric Conductivity; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009865:Oocytes / Q000502:physiology; D017354:Point Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection; D014960:X Chromosome; D014982:Xenopus laevis; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D011994:Recombinant Proteins; D013779:Tetrodotoxin; D000097002:Gap Junction beta-1 Protein