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 unkn own. Here, we report that eight of nine CMTX mutations investigated fo rm channels with measurable electrical conductance. Single-channel stu dies of two mutations demonstrate reduced junctional permeability caus ed by a decrease in either pore size (S26L) or open channel probabilit y (M34T) that favors residency in a low-conductance substate. Permeati on of second messengers such as cAMP through reflexive gap junctions b etween adjacent cytoplasmic loops of myelinating Schwann cells is like ly to be reduced or absent in these channels. We propose that CMTX mut ations impair the transduction of signals arising from normal glial-ne uronal interactions and thereby cause demyelination and axonal degener ation.