Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

Maruthappu, Thiviyani; Pósafalvi, Anna; Castelletti, Silvia; Delaney, Paul J.; Syrris, Petros; O’Toole, Edel A.; Green, Kathleen J.; Elliott, Perry; Lambiase, Pier D.; Tinker, Andrew; McKenna, William J.; Kelsell, David P.

doi:10.1111/bjd.17388

Cited by 39 publications

(51 citation statements)

References 25 publications

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“…The first genetic studies of AC arose from the study of autosomal recessive AC syndromes associated with a skin disease (palmoplantar keratoderma) and woolly hair . Better understanding of desmosomal function and disease mechanisms in the skin from AC patients may provide insights into AC pathogenesis and potential therapeutic strategies.…”

Section: What Is the Role Of The Desmosome In Arrhythmogenic Cardiomymentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

109

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It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

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Section: What Is the Role Of The Desmosome In Arrhythmogenic Cardiomymentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

109

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“…and cAMP signaling (10)(11)(12), whereas others, such as SRC, appear not to be central for the disease (13). The context of pemphigus is relevant to AC for 2 reasons: First, AC is known to occur in syndromes that affect the skin and its appendices when specific mutations in genes coding for PG or DP are causative (14)(15)(16). Second, recently, it has been proposed that different mutations in desmosomal genes causing AC can induce the formation of autoantibodies against cardiomyocyte antigens, including DSG2, which are pathogenic and thus may aggravate the disease (17,18).…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin

et al. 2020

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“…Together with adherens junctions and tight junctions, desmosomes enable integration and stratification of epithelia, whilst ensuring that barrier function is maintained at all times and also that damaged tissue cells can be replaced. Loss of desmosome function is linked to severe diseases, particularly in mechanically challenged tissues such as skin and cardiac muscle (reviewed by (Chidgey and Dawson, 2007; Delmar and McKenna, 2010; Dusek and Attardi, 2011; Ishida-Yamamoto and Igawa, 2014; Maruthappu et al, 2019; Spindler et al, 2018; Thomason et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Desmosomal dualism: the core is stable while plakophilin is dynamic

Huppert

Liebl

et al. 2021

Preprint

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Desmosomes, strong cell-cell junctions of epithelia and cardiac muscle, link intermediate filaments to cell membranes and mechanically integrate cells across tissues, dissipating mechanical stress. They comprise 5 major protein classes - desmocollins and desmogleins (the desmosomal cadherins), plakoglobin, plakophilins and desmoplakin - whose individual contribution to the structure and turnover of desmosomes is poorly understood. Using live-cell imaging together with FRAP and FLAP we show that desmosomes consist of two contrasting protein fractions or modules: a very stable desmosomal core of desmosomal cadherins and plakoglobin, and a highly mobile plakophilin. As desmosomes mature from calcium-dependence to calcium-independent hyper-adhesion, core stability increases, but Pkp2a remains highly mobile. Desmoplakin is initially mobile but stabilises with hyper-adhesion. We show that desmosome down-regulation during growth factor-induced cell scattering proceeds by internalisation of whole desmosomes, which still retain a stable core and highly mobile Pkp2a. This molecular mobility of Pkp2a suggests a transient and probably regulatory role for Pkp2a in the desmosome.

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Loss‐of‐function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype

Abstract: This summary relates to https://doi.

Cited by 39 publications

References 25 publications

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin

Desmosomal dualism: the core is stable while plakophilin is dynamic

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