Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43

Isaac E. García, Jaime Maripillán, Oscar Jara, Ricardo Ceriani, Angelina Palacios-Muñoz, Jayalakshmi Ramachandran, Pablo Olivero, Tomas Perez-Acle, Carlos González, Juan C. Sáez, Jorge E. Contreras, Agustín D. Martínez

Resultado de la investigación: Article

39 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1338-1347
Número de páginas10
PublicaciónJournal of Investigative Dermatology
Volumen135
N.º5
DOI
EstadoPublished - 22 may 2015

Huella dactilar

Connexin 43
Connexins
Gap Junctions
Mutation
Deafness
Skin
Oligomerization
Cell Membrane Permeability
Connexin 26
Keratitis-Ichthyosis-Deafness Syndrome
Medical Genetics
Adenosine Triphosphate
Cell membranes
Oligomers
Phenotype

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Citar esto

García, Isaac E. ; Maripillán, Jaime ; Jara, Oscar ; Ceriani, Ricardo ; Palacios-Muñoz, Angelina ; Ramachandran, Jayalakshmi ; Olivero, Pablo ; Perez-Acle, Tomas ; González, Carlos ; Sáez, Juan C. ; Contreras, Jorge E. ; Martínez, Agustín D. / Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43. En: Journal of Investigative Dermatology. 2015 ; Vol. 135, N.º 5. pp. 1338-1347.
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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.",
author = "Garc{\'i}a, {Isaac E.} and Jaime Maripill{\'a}n and Oscar Jara and Ricardo Ceriani and Angelina Palacios-Mu{\~n}oz and Jayalakshmi Ramachandran and Pablo Olivero and Tomas Perez-Acle and Carlos Gonz{\'a}lez and S{\'a}ez, {Juan C.} and Contreras, {Jorge E.} and Mart{\'i}nez, {Agust{\'i}n D.}",
year = "2015",
month = "5",
day = "22",
doi = "10.1038/jid.2015.20",
language = "English",
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García, IE, Maripillán, J, Jara, O, Ceriani, R, Palacios-Muñoz, A, Ramachandran, J, Olivero, P, Perez-Acle, T, González, C, Sáez, JC, Contreras, JE & Martínez, AD 2015, 'Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43', Journal of Investigative Dermatology, vol. 135, n.º 5, pp. 1338-1347. https://doi.org/10.1038/jid.2015.20

Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43. / García, Isaac E.; Maripillán, Jaime; Jara, Oscar; Ceriani, Ricardo; Palacios-Muñoz, Angelina; Ramachandran, Jayalakshmi; Olivero, Pablo; Perez-Acle, Tomas; González, Carlos; Sáez, Juan C.; Contreras, Jorge E.; Martínez, Agustín D.

En: Journal of Investigative Dermatology, Vol. 135, N.º 5, 22.05.2015, p. 1338-1347.

Resultado de la investigación: Article

TY - JOUR

T1 - Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43

AU - García, Isaac E.

AU - Maripillán, Jaime

AU - Jara, Oscar

AU - Ceriani, Ricardo

AU - Palacios-Muñoz, Angelina

AU - Ramachandran, Jayalakshmi

AU - Olivero, Pablo

AU - Perez-Acle, Tomas

AU - González, Carlos

AU - Sáez, Juan C.

AU - Contreras, Jorge E.

AU - Martínez, Agustín D.

PY - 2015/5/22

Y1 - 2015/5/22

N2 - 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.

AB - 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.

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