: Connexin 32 (Cx32) belongs to a gene family of at least 15 members (in mammals), all of which encode gap junction proteins. Six connexins oligomerize to form a hemi-channel (or connexon), which forms a channel when apposed to another hemi-channel on an adjacent membrane. Gap junctions allow the diffusion of ions and small molecules, typically with a molecular mass less than 1000 Da. Individual hemichannels can be composed of more than one connexin (heterotypic connexons), and hemichannels composed of different connexins can also form channels (heterotypic gap junctions). In a series of papers, my colleagues and I have investigated how mutations in the human Cx32 gene cause the X-linked form of Charcot-Marie-Tooth disease (CMTX). This is the second most common form of inherited demyelinating neuropathy (CMT type 1), a genetically heterogenous group that collectively is among the most common inherited neurological diseases. We were the first to show that mutations cause CMTX, that Cx32 is localized to incisures and paranodes (regions of the Schwann cell (SC) myelin sheath that are composed on non-compact myelin) and that the SC myelin sheath contains functional gap junctions. Of particular relevance to this grant, some mutations result in loss of the protein, or alter trafficking so that the mutant protein does not reach the cell membrane. Of the mutants that reach the cell membrane, some fail to form functional gap junctions (communication-incompetent), whereas others are communication-competent. We have made transgenic mice that express wild type or two different mutant Cx32 alleles and found that trafficking of the two mutant proteins was similar to that in transfected cells. One of the mutants, Arg142Trp, has a dominant-negative effect on wild type Cx32: not only does the mutant protein """"""""hang up"""""""" in the Golgi, it also causes the wild type protein to accumulate there, too. The goals of this competing renewal are as follows: (1) to determine whether the effects of CMTX mutations are autonomous to myelinating Schwann cells; (2) to determine how Cx32 mutants that form gap junctions in vitro disrupt the function of myelinating SC; (3) to determine whether myelinating SC express other connexins and whether other connnexins can substitute for Cx32 in myelinating SC. The results will elucidate how gap junction proteins are assembled and function in myelinating SC, provide fundamental information on the molecular pathophysiology of CMTX, and illuminate how mutations in other gap junction proteins cause disease.
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