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Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2016 Jan 15; Vol. 25 (2), pp. 348-57. Date of Electronic Publication: 2015 Nov 24. - Publication Year :
- 2016
-
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.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Amino Acid Sequence
Cardiomyopathies metabolism
Child
Child, Preschool
Connexin 43 metabolism
Desmoplakins metabolism
Female
Humans
Infant
Male
Molecular Sequence Data
Myocardium metabolism
Protein Transport
Sequence Alignment
Skin metabolism
Skin Diseases, Genetic metabolism
Syndrome
Cardiomyopathies genetics
Desmoplakins genetics
Desmosomes metabolism
Mutation, Missense
Skin Diseases, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 25
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26604139
- Full Text :
- https://doi.org/10.1093/hmg/ddv481