Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders

George Bakirtzis, Rukhsana Choudhry, Trond Aasen, Leonard Shore, Ken Brown, Sheila Bryson, Stephen Forrow, Laurence Tetley, Malcolm E. Finbow, Malcolm B. Hodgins

Research output: Contribution to journalArticle

Abstract

To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusPublished - 1 Jul 2003

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Connexins
Keratinocytes
Epidermis
Keratin-10
Intercellular Junctions
In Situ Nick-End Labeling
Transgenes
Skin Diseases
Transgenic Mice
Vohwinkel syndrome
Connexin 26
Electron Microscopy
Cytoplasm
Cell Death
Parturition
Staining and Labeling
Phenotype
Light
Mutation
Proteins

Cite this

Bakirtzis, George ; Choudhry, Rukhsana ; Aasen, Trond ; Shore, Leonard ; Brown, Ken ; Bryson, Sheila ; Forrow, Stephen ; Tetley, Laurence ; Finbow, Malcolm E. ; Hodgins, Malcolm B. / Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. In: Human Molecular Genetics. 2003.
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title = "Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders",
abstract = "To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.",
author = "George Bakirtzis and Rukhsana Choudhry and Trond Aasen and Leonard Shore and Ken Brown and Sheila Bryson and Stephen Forrow and Laurence Tetley and Finbow, {Malcolm E.} and Hodgins, {Malcolm B.}",
note = "Originally published in: Human Molecular Genetics (2004), 12 (14), pp.1737-1744.",
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Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders. / Bakirtzis, George; Choudhry, Rukhsana; Aasen, Trond; Shore, Leonard; Brown, Ken; Bryson, Sheila; Forrow, Stephen; Tetley, Laurence; Finbow, Malcolm E.; Hodgins, Malcolm B.

In: Human Molecular Genetics, 01.07.2003.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders

AU - Bakirtzis, George

AU - Choudhry, Rukhsana

AU - Aasen, Trond

AU - Shore, Leonard

AU - Brown, Ken

AU - Bryson, Sheila

AU - Forrow, Stephen

AU - Tetley, Laurence

AU - Finbow, Malcolm E.

AU - Hodgins, Malcolm B.

N1 - Originally published in: Human Molecular Genetics (2004), 12 (14), pp.1737-1744.

PY - 2003/7/1

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N2 - To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

AB - To investigate the role of connexins in dominantly inherited skin disease, transgenic mice were produced which expressed mutant connexin 26 [gjb2/connexin 26(D66H)], from a keratin 10 promoter, exclusively in the suprabasal epidermis (the cells in which Connexin 26 is up-regulated in epidermal hyperproliferative states). From soon after birth, the mice exhibited a keratoderma similar to that in humans carrying the Connexin 26(D66H) mutation (true Vohwinkel syndrome). Transgene expression was associated with loss of Connexin 26 and Connexin 30 from epidermal keratinocyte intercellular junctions and accumulation in cytoplasm. Light and electron microscopy showed marked thickening of the epidermal cornified layers and increased epidermal TUNEL staining, indicative of premature keratinocyte programmed cell death. The K10Connexin 26(D66H) mouse may provide a valuable model to study the role of gap-junctional intercellular communication in epidermal differentiation. Similarities in phenotype between individuals (man and mouse) carrying Connexin 26(D66H) and those carrying insertional mutants of Loricrin, a major cornified envelope protein of the epidermis, suggest a possible link between connexin function and cornified envelope formation.

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DO - 10.1093/hmg/ddg183

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SN - 0964-6906

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