Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome

• Published in: Human molecular genetics Vol. 25; no. 2; pp. 348 - 357
• Main Authors: Boyden, Lynn M., Kam, Chen Y., Hernández-Martín, Angela, Zhou, Jing, Craiglow, Brittany G., Sidbury, Robert, Mathes, Erin F., Maguiness, Sheilagh M., Crumrine, Debra A., Williams, Mary L., Hu, Ronghua, Lifton, Richard P., Elias, Peter M., Green, Kathleen J., Choate, Keith A.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.01.2016
• Subjects: Amino Acid Sequence; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Child; Child, Preschool; Connexin 43 - metabolism; Desmoplakins - genetics; Desmoplakins - metabolism; Desmosomes - metabolism; Female; Humans; Infant; Male; Molecular Sequence Data; Mutation, Missense; Myocardium - metabolism; Protein Transport; Sequence Alignment; Skin - metabolism; Skin Diseases, Genetic - genetics; Skin Diseases, Genetic - metabolism; Syndrome
• DOI: 10.1093/hmg/ddv481
• ISSN: 0964-6906; 1460-2083

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.