Dominant De Novo Mutations in GJA1 Cause Erythrokeratodermia Variabilis et Progressiva, without Features of Oculodentodigital Dysplasia.
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.
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Lynn M
LM
Boyden
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Brittany G
BG
Craiglow
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Jing
J
Zhou
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
Ronghua
R
Hu
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Erin C
EC
Loring
Departments of Dermatology and Pediatrics, Columbia University, New York, New York, USA.
Kimberly D
KD
Morel
Departments of Dermatology and Pediatrics, Columbia University, New York, New York, USA.
Christine T
CT
Lauren
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Richard P
RP
Lifton
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Kaya
K
Bilguvar
Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Amy S
AS
Paller
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address: keith.choate@yale.edu.
Keith A
KA
Choate
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018031:Connexin 43 / Q000235:genetics*; D017630:Connexins / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D018450:Disease Progression; D056266:Erythrokeratodermia Variabilis / Q000235:genetics*; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012871:Skin Diseases / Q000235:genetics*; D013576:Syndactyly / Q000235:genetics*; D014071:Tooth Abnormalities / Q000235:genetics*
D018031:Connexin 43; D017630:Connexins; C500216:GJA1 protein, human