Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: Characterization of 14 C×32 mutations in 35 families

Rouger, H.; LeGuern, Eric; Birouk, N.; Gouider, Riadh; Tardieu, S; Plassart, E; Gugenheim, Michel; Vallat, Jean‐Michel; Louboutin, Jean‐Pierre; Bouché, P; Agid, Yves; Brice, Alexis

doi:10.1002/(sici)1098-1004(1997)10:6<443::aid-humu5>3.0.co;2-e

Cited by 59 publications

(20 citation statements)

References 31 publications

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“…5). The same mutation was previously reported in the homologous residue of the gene for Cx32 (residue F141L) in X-linked Charcot-Marie-Tooth disease (Rouger et al 1997) and of the gene for Cx31 (residue F137L) in a sporadic case of severe EKV (Richard et al 2000), providing evidence for the crucial function of this amino acid residue. Indeed, the M3 domain is known to be involved in the formation of the wall of the gap-junction pore and is at least partly implicated in the voltage gating of the channels.…”

Section: Figuresupporting

confidence: 78%

Mutation in the Gene for Connexin 30.3 in a Family with Erythrokeratodermia Variabilis

Macari¹,

Landau²,

Cousin³

et al. 2000

Am. J Hum. Genet.

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Erythrokeratodermia variabilis (EKV) is an autosomal dominant keratinization disorder characterized by migratory erythematous lesions and fixed keratotic plaques. All families with EKV show mapping to chromosome 1p34-p35, and mutations in the gene for connexin 31 (Cx31) have been reported in some but not all families. We studied eight affected and three healthy subjects in an Israeli family, of Kurdish origin, with EKV. After having mapped the disorder to chromosome 1p34-p35, we found no mutations in the genes for Cx31, Cx31.1, and Cx37. Further investigation revealed a heterozygous TrC transition leading to the missense mutation (F137L) in the human gene for Cx30.3 that colocalizes on chromosome 1p34-p35. This nucleotide change cosegregated with the disease and was not found in 200 alleles from normal individuals. This mutation concerns a highly conserved phenylalanine, in the third transmembrane region of the Cx30.3 molecule, known to be implicated in the wall formation of the gap-junction pore. Our results show that mutations in the gene for Cx30.3 can be causally involved in EKV and point to genetic heterogeneity of this disorder. Furthermore, we suggest that our family presents a new type of EKV because of the hitherto unreported association with erythema gyratum repens.Connexins (denoted by the prefix "Cx") are a family of polypeptides that form the subunits of the gap-junction channels. Members of the connexin family are characterized by four hydrophobic transmembrane domains (M1-M4) that are linked by one cytoplasmic and two extracellular (E1 and E2) loops. The N and C termini are located on the cytoplasmic membrane face. Extracellular-loop and transmembrane domains display the highest homology between the connexin family members, whereas the cytoplasmic loop and the C-terminal region are highly variable. Six connexin polypeptides assemble into a connexon, a hemichannel that interacts with its counterpart on adjacent cells to form a complete intercellular channel, thereby connecting the cytoplasm of neighboring cells (Yeager and Nicholson 1996). Gap junctions are composed of numerous aggregated con-

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Section: Figuresupporting

confidence: 78%

Mutation in the Gene for Connexin 30.3 in a Family with Erythrokeratodermia Variabilis

Macari¹,

Landau²,

Cousin³

et al. 2000

Am. J Hum. Genet.

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“…Nerve conduction velocities are typically in 30 -40 m/s in affected males and 30 -50 m/s in affected females (Nicholson and Nash, 1993;Rouger et al, 1997;Birouk et al, 1998;Hahn et al, 1999;Senderek et al, 1999); this is faster than the 20 m/s typically seen in CMT1A patients . In addition, electrophysiological studies pronounced loss of distal motor axons in CMT1X (Rozear et al, 1987;Hahn et al, 1990Hahn et al, , 1999Nicholson and Nash, 1993;Rouger et al, 1997;Birouk et al, 1998;Senderek et al, 1999). Finally, nerve biopsies show more axonal loss and less remyelination than is typically seen in CMT1A or CMT1B (Sander et al, 1998;Hahn et al, 2001).…”

Section: Discussionmentioning

confidence: 82%

Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Scherer¹,

Xu²,

Messing³

et al. 2005

J. Neurosci.

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Mutations in Gap Junction ␤1 (GJB1), the gene encoding the gap junction protein connexin32 (Cx32), cause the X-linked form of Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells. Male mice expressing the human transgene were crossed with female Gjb1/cx32-null mice; the resulting male offspring were all cx32-null (on the X chromosome), and one-half were transgene positive. In these transgenic mice, all of the Cx32 was derived from the expression of the transgene and was found in the sciatic nerve but not in the spinal cord or the liver. Furthermore, the Cx32 protein was properly localized (within incisures and paranodes) in myelinating Schwann cells. Finally, the expression of human Cx32 protein "rescued" the phenotype of cx32-null mice, because the transgenic mice have significantly fewer demyelinated or remyelinated axons than their nontransgenic littermates. These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X.

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“…F137L affects another phylogenetically conserved residue in M3 of Cx31. A similar substitution of an analogous residue of GJB1 (F141L) has been implicated in X-linked Charcot-Marie-Tooth disease (116), supporting a critical function of phenylalanine at this position. The M3 domain is assumed to be associated with the voltage gate of Cx channels (27).…”

mentioning

confidence: 74%

Connexins: a connection with the skin

Richard

2000

Experimental Dermatology

163

112

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The intercellular signaling system mediated by connexin chanInstitute of Molecular Medicine, Thomas nels is crucial for maintaining tissue homeostasis, growth control, developJefferson University, Philadelphia, PA, USA ment, and synchronized response of cells to stimuli. This review summarizes the structure, assembly, and properties of the components of the complex and diverse connexin system, and their biological functions in

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Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: Characterization of 14 C×32 mutations in 35 families

Cited by 59 publications

References 31 publications

Mutation in the Gene for Connexin 30.3 in a Family with Erythrokeratodermia Variabilis

Mutation in the Gene for Connexin 30.3 in a Family with Erythrokeratodermia Variabilis

Transgenic Expression of HumanConnexin32in Myelinating Schwann Cells Prevents Demyelination inConnexin32-Null Mice

Connexins: a connection with the skin

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