title: Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.
abstract: Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.
authors.affiliation: Department of Genetics.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Boyden
authors.affiliation: Departments of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Chen Y
authors.initials: CY
authors.lastname: Kam
authors.affiliation: Department of Dermatology, Hospital Infantil del Niño Jesús, Madrid, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Hernández-Martín
authors.affiliation: Department of Dermatology and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Dermatology and.
authors.forename: Brittany G
authors.initials: BG
authors.lastname: Craiglow
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Sidbury
authors.affiliation: Department of Dermatology, UCSF School of Medicine, San Francisco, CA, USA and.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Mathes
authors.affiliation: Department of Dermatology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Sheilagh M
authors.initials: SM
authors.lastname: Maguiness
authors.affiliation: Department of Dermatology, UCSF School of Medicine, San Francisco, CA, USA and.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Crumrine
authors.affiliation: Department of Dermatology, UCSF School of Medicine, San Francisco, CA, USA and.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Williams
authors.affiliation: Department of Dermatology and.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Genetics.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Dermatology, UCSF School of Medicine, San Francisco, CA, USA and.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Departments of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Department of Genetics, Department of Dermatology and Department of Pathology, Yale University School of Medicine, New Haven, CT, USA, keith.choate@yale.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Choate
mesh_terms: D000595:Amino Acid Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018031:Connexin 43 / Q000378:metabolism; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism; D021381:Protein Transport; D016415:Sequence Alignment; D012867:Skin / Q000378:metabolism; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D018031:Connexin 43; C495294:DSP protein, human; D051180:Desmoplakins; C500216:GJA1 protein, human