title: Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43.
abstract: Mutations in Cx26 gene are found in most cases of human genetic deafness. Some mutations produce syndromic deafness associated with skin disorders, like the Keratitis-Ichthyosis-Deafness syndrome (KID). Because in the human skin connexin 26 (Cx26) is co-expressed with other connexins, like Cx43 and Cx30, and as the KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins. Indeed, some Cx26 syndromic mutations showed gap junction dominant negative effect when co-expressed with wild-type connexins, including Cx26 and Cx43. The nature of these interactions and the consequences on hemichannels and gap junction channel (GJC) functions remain unknown. In this study, we demonstrate that syndromic mutations, at the N terminus segment of Cx26, change connexin oligomerization compatibility, allowing aberrant interactions with Cx43. Strikingly, heteromeric oligomer formed by Cx43/Cx26 (syndromic mutants) shows exacerbated hemichannel activity but nonfunctional GJCs; this also occurs for those Cx26 KID mutants that do not show functional homomeric hemichannels. Heterologous expression of these hyperactive heteromeric hemichannels increases cell membrane permeability, favoring ATP release and Ca(2+) overload. The functional paradox produced by oligomerization of Cx43 and Cx26 KID mutants could underlie the severe syndromic phenotype in human skin.
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Isaac E
authors.initials: IE
authors.lastname: García
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Maripillán
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Oscar
authors.initials: O
authors.lastname: Jara
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ceriani
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Angelina
authors.initials: A
authors.lastname: Palacios-Muñoz
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Ramachandran
authors.affiliation: Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Olivero
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile; Fundación Ciencia and Vida, Santiago, Chile.
authors.forename: Tomas
authors.initials: T
authors.lastname: Perez-Acle
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: González
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile; Departamento de Fisiología, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Sáez
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Contreras
authors.affiliation: Laboratorio de Conexinas y Panexinas, Centro Interdisciplinario de Neurociencias de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile. Electronic address: agustin.martinez@uv.cl.
authors.forename: Agustín D
authors.initials: AD
authors.lastname: Martínez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D003638:Deafness / Q000235:genetics* / Q000503:physiopathology; D017629:Gap Junctions / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000503:physiopathology; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D007634:Keratitis / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; D007473:Ion Channels; D000072259:Connexin 26; D000255:Adenosine Triphosphate; D002118:Calcium