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Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.

Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, Lifton RP, Bilguvar K, Yale Center for Mendelian GenomicsPaller AS, Choate KA - J. Invest. Dermatol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

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.

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Figurate erythema and darkening of the skin in EKVP due to GJA1 mutationAll subjects report figurate erythema and have experienced progressive skin darkening. (a) In subject 101-1, figurate erythema is present on the back, flank, arm, and upper thigh. (b) Subject 102-1 shows thick, corrugated keratoderma with darkening prominent on the neck, forearm, axilla, and abdomen. There is a patch of erythema on the wrist. (c) In subject 103-1, figurate erythema is present on the upper and lower back. Notably, subject 103-1 reports that figurate erythema became more frequent and prominent at age 10 years but was present throughout childhood. Treatment with acitretin has reduced scaling, but hyperpigmentation is prominent on the flanks, shoulders, and neck. In all cases, erythema is induced by stress and warm conditions and can be accompanied by a stinging or burning sensation.
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Figure 3: Figurate erythema and darkening of the skin in EKVP due to GJA1 mutationAll subjects report figurate erythema and have experienced progressive skin darkening. (a) In subject 101-1, figurate erythema is present on the back, flank, arm, and upper thigh. (b) Subject 102-1 shows thick, corrugated keratoderma with darkening prominent on the neck, forearm, axilla, and abdomen. There is a patch of erythema on the wrist. (c) In subject 103-1, figurate erythema is present on the upper and lower back. Notably, subject 103-1 reports that figurate erythema became more frequent and prominent at age 10 years but was present throughout childhood. Treatment with acitretin has reduced scaling, but hyperpigmentation is prominent on the flanks, shoulders, and neck. In all cases, erythema is induced by stress and warm conditions and can be accompanied by a stinging or burning sensation.

Mentions: Subject 101-1 is a 32-month-old boy who had no clinical phenotype until the age of 5 months. He then developed thick brown-gray scale on frictional surfaces (Figure 1a), as well as progressive darkening of his dorsal hands, arms, legs, and face. His palmoplantar surfaces and digits became pink and then markedly hyperkeratotic (Figure 2a), and migrating areas of transient figurate erythema overlay the generalized scaling (Figure 3a).


Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.

Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, Lifton RP, Bilguvar K, Yale Center for Mendelian GenomicsPaller AS, Choate KA - J. Invest. Dermatol. (2014)

Figurate erythema and darkening of the skin in EKVP due to GJA1 mutationAll subjects report figurate erythema and have experienced progressive skin darkening. (a) In subject 101-1, figurate erythema is present on the back, flank, arm, and upper thigh. (b) Subject 102-1 shows thick, corrugated keratoderma with darkening prominent on the neck, forearm, axilla, and abdomen. There is a patch of erythema on the wrist. (c) In subject 103-1, figurate erythema is present on the upper and lower back. Notably, subject 103-1 reports that figurate erythema became more frequent and prominent at age 10 years but was present throughout childhood. Treatment with acitretin has reduced scaling, but hyperpigmentation is prominent on the flanks, shoulders, and neck. In all cases, erythema is induced by stress and warm conditions and can be accompanied by a stinging or burning sensation.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4430428&req=5

Figure 3: Figurate erythema and darkening of the skin in EKVP due to GJA1 mutationAll subjects report figurate erythema and have experienced progressive skin darkening. (a) In subject 101-1, figurate erythema is present on the back, flank, arm, and upper thigh. (b) Subject 102-1 shows thick, corrugated keratoderma with darkening prominent on the neck, forearm, axilla, and abdomen. There is a patch of erythema on the wrist. (c) In subject 103-1, figurate erythema is present on the upper and lower back. Notably, subject 103-1 reports that figurate erythema became more frequent and prominent at age 10 years but was present throughout childhood. Treatment with acitretin has reduced scaling, but hyperpigmentation is prominent on the flanks, shoulders, and neck. In all cases, erythema is induced by stress and warm conditions and can be accompanied by a stinging or burning sensation.
Mentions: Subject 101-1 is a 32-month-old boy who had no clinical phenotype until the age of 5 months. He then developed thick brown-gray scale on frictional surfaces (Figure 1a), as well as progressive darkening of his dorsal hands, arms, legs, and face. His palmoplantar surfaces and digits became pink and then markedly hyperkeratotic (Figure 2a), and migrating areas of transient figurate erythema overlay the generalized scaling (Figure 3a).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

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.

Show MeSH
Related in: MedlinePlus