Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia

Yale Center for Mendelian Genomics

doi:10.1038/jid.2014.485

Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia

Yale Center for Mendelian Genomics

Dermatology

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

Original language	English (US)
Pages (from-to)	1540-1547
Number of pages	8
Journal	Journal of Investigative Dermatology
Volume	135
Issue number	6
DOIs	https://doi.org/10.1038/jid.2014.485
State	Published - Jan 1 2015

Funding

We thank the EKVP subjects and their families for their invaluable contribution to this work; Jonathan Levinsohn, Young Lim, Leonard Milstone, and Haris Mirza for critical review of the manuscript; and Christopher Castaldi, Vincent Klump, Shrikant Mane, Peggy Myung, Carol Nelson-Williams, and Irina Tikhonova for technical assistance. This work was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award and a Research Grant from the Foundation for Ichthyosis & Related Skin Types (FIRST), funded by the Lennox Foundation to KAC; a Dermatology Foundation Pediatric Dermatology Fellowship, FIRST funds, and National Institutes of Health funds to BGC (NIH T32 AR007016); the Yale Center for Mendelian Genomics (NIH U54 HG006504); and the Yale Center for Clinical Investigation (NIH UL1 TR000142). We thank the EKVP subjects and their families for their invaluable contribution to this work; Jonathan Levinsohn, Young Lim, Leonard Milstone, and Haris Mirza for critical review of the manuscript; and Christopher Castaldi, Vincent Klump, Shrikant Mane, Peggy Myung, Carol Nelson-Williams, and Irina Tikhonova for technical assistance. This work was supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award and a Research Grant from the Foundation for Ichthyosis & Related Skin Types (FIRST), funded by the Lennox Foundation to KAC; a Dermatology Foundation Pediatric Dermatology Fellowship, FIRST funds, and National Institutes of Health funds to BGC (NIH T32 AR007016); the Yale Center for Mendelian Genomics (NIH U54 HG006504); and the Yale Center for Clinical Investigation (NIH UL1 TR000142).

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1038/jid.2014.485

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@article{e0b80a06d0e64b7f91113a8ff0c577f7,

title = "Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia",

abstract = "Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.",

author = "{Yale Center for Mendelian Genomics} and Boyden, {Lynn M.} and Craiglow, {Brittany G.} and Jing Zhou and Ronghua Hu and Loring, {Erin C.} and Morel, {Kimberly D.} and Lauren, {Christine T.} and Lifton, {Richard P.} and Kaya Bilguvar and Paller, {Amy S.} and Choate, {Keith A.}",

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year = "2015",

month = jan,

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doi = "10.1038/jid.2014.485",

language = "English (US)",

volume = "135",

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journal = "Journal of Investigative Dermatology",

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AU - Yale Center for Mendelian Genomics

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AU - Craiglow, Brittany G.

AU - Zhou, Jing

AU - Hu, Ronghua

AU - Loring, Erin C.

AU - Morel, Kimberly D.

AU - Lauren, Christine T.

AU - Lifton, Richard P.

AU - Bilguvar, Kaya

AU - Paller, Amy S.

AU - Choate, Keith A.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

AB - Genetic investigation of inherited skin disorders has informed the understanding of skin self-renewal, differentiation, and barrier function. Erythrokeratodermia variabilis et progressiva (EKVP) is a rare, inherited skin disease that is characterized by transient figurate patches of erythema, localized or generalized scaling, and frequent palmoplantar keratoderma. By using exome sequencing, we show that de novo missense mutations in GJA1 (gap junction protein alpha 1) cause EKVP. The severe, progressive skin disease in EKVP subjects with GJA1 mutations is distinct from limited cutaneous findings rarely found in the systemic disorder oculodentodigital dysplasia, also caused by dominant GJA1 mutations. GJA1 encodes connexin 43 (Cx43), the most widely expressed gap junction protein. We show that the GJA1 mutations in EKVP subjects lead to disruption of Cx43 membrane localization and aggregation within the Golgi. These findings reveal a critical role for Cx43 in epidermal homeostasis, and they provide evidence of organ-specific pathobiology resulting from different mutations within GJA1.

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Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia

Abstract

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