Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

Lynn M. Boyden, Chen Y. Kam, Angela Hernández-Martín, Jing Zhou, Brittany G. Craiglow, Robert Sidbury, Erin F. Mathes, Sheilagh M. Maguiness, Debra A. Crumrine, Mary L. Williams, Ronghua Hu, Richard P. Lifton, Peter M. Elias, Kathleen J. Green, Keith A. Choate*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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, afinding not previously associated with erythrokeratodermia.We show that de novomissensemutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, whichwe termerythrokeratodermia-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. Thoughmutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severewhole-body erythrokeratodermia,with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndromefeaturing erythrokeratodermia and cardiomyopathy to the spectrum of disease caused bymutationin DSP, andidentifya specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

Original languageEnglish (US)
Pages (from-to)348-357
Number of pages10
JournalHuman molecular genetics
Issue number2
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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