Connexin channels in Schwann cells and the development of the X-linked form of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease comprises a group of genetically heterogenous disorders of the peripheral nervous system. The X-linked form of Charcot-Marie-Tooth (CMTX) is associated with mutations in the gene encoding the gap junction protein connexin32 (Cx32), which is expressed in Schwann cells. Immunocytochemical evidence suggests that Cx32 is localized to the incisures of Schmidt-Lanterman and the paranodes of myelinating Schwann cells, where it appears to form reflexive gap junctions. It is currently thought that this cytoplasmic continuity provides a much shorter diffusion pathway for the transport of ions, metabolites and second messenger molecules through intracellular channels between the adaxonal and peri-nuclear regions of Schwann cells, across the myelin sheath. This review summarizes our current understanding of the role of connexins in Schwann cells and focuses on the lessons for channel function and disease pathophysiology derived from the functional analysis of Cx32 mutations. One of the most intriguing aspects emerging from this work is that several mutations retain functional competence, although the mutated channels exhibit altered gating properties. This suggests that partial and/or selective disruption of the radial communication pathway formed by Cx32 is sufficient to cause a functional deficit and lead to the development of CMTX. The next challenge will be to define, at the molecular level, the sequence of events involved in the disease process. The presence of a group of functional mutations should help understand the cellular basis of CMTX, by allowing the identification of the specific molecules that need to be exchanged through Cx32 channels, but are excluded from the mutated ones. (C) 2000 Elsevier Science B.V.link_to_subscribed_fulltex

Three genes, four demyelinating neuropathies: First genotype/phenotype correlations | Trois genes et quatre neuropathies peripheriques myelinques: Premieres correlations genotype/phenotype

In most vertebrates, axons are usually ensheathed by myelin, a multi-lamellar structure that ensures the fidelity of nerve transmission and increases considerably nerve conduction velocity along the fibers. In the peripheral nervous system (PNS), myelin is formed by the extension of the plasma membrane of Schwann cells that wrap in spiral as many as 50 layers of double membrane structures around the axon. The myelin sheaths consist mostly of compact myelin that expresses a distinct set of structural proteins, namely myelin protein zero (P0), which is the most abundant component, peripheral myelin protein 22 (PMP22) and myelin basic protein. PNS compact myelin is interrupted by regions filled with cytoplasm, the incisures of Schmidt-Lanterman. These and the paranodal regions of Schwann cells express a distinct set of proteins that include myelin-associated glycoprotein and connexin32 (Cx32). It has now been demonstrated that genetic abnormalities in the genes encoding PMP22, P0 and Cx32, are responsible for the vast majority of demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth disease type 1, X-linked Charcot-Marie-Tooth, Dejerine-Sottas syndrome, hereditary neuropathy with liability to pressure palsies and congenital hypomyelination. PMP22 is an integral membrane protein whose function is still poorly understood. P0 is a cell adhesion protein that contributes a sort of adhesive tape that holds together the extracellular leaflets of compact myelin. Cx32 is a channel-forming protein that is thought to provide the basis for a radial diffusional pathway of signaling molecules and metabolites across the myelin layers. Recent studies on the molecular structure and cell biology of these three pivotal proteins for myelin homeostasis have begun to shed light on some of the pathophysiological mechanisms that are specific to each syndrome.link_to_subscribed_fulltex

Connexin32 in the peripheral nervous system: Functional analysis of mutations associated with X-linked Charcot-Marie-Tooth syndrome and implications for the pathophysiology of the disease

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First genetic evidence of GABAA receptor dysfunction in epilepsy: A mutation in the γ2-subunit gene

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively1-6. Disruption of GABAergic neurotransmission mediated by γ-aminobutyric acid (GABA) has been implicated in epilepsy for many decades7. We now report a K289M mutation in the GABAA receptor γ2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes1,2. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABAA receptor is directly involved in human idiopathic epilepsy.link_to_subscribed_fulltex

Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness

The connexins are a family of at least 20 homologous proteins in humans that form aqueous channels connecting the interiors of coupled cells and mediating electrical and chemical communication. Mutations in the gene for human connexin 31 (hCx31) are associated with disorders of the skin and auditory system. Alterations in functional properties of Cx31 junctions are likely to play a role in these diseases; nonetheless, little is known about the properties of the wild-type channels. Here we show that hCx31 channels, like other connexin channels, are gated by voltage and close at low pH and when exposed to long-chain alkanols. Single-channel conductance of the fully open channel is ≈85 pS, and it is permeable to Lucifer yellow, Alexa Fluor(350), ethidium bromide, and DAPI, which have valences of −2, −1, +1, and +2, respectively. In contrast to what has been reported for mouse Cx31, hCx31 appears to form functional heterotypic channels with all four connexins tested, Cx26, Cx30, Cx32, and Cx45. These findings provide an important first step in evaluating the pathogenesis of inherited human diseases associated with mutations in the gene for Cx31