Skin and heart: une liaison dangereuse

Bolling, Maria C.; Jonkman, Marcel F.

doi:10.1111/j.1600-0625.2009.00908.x

Cited by 54 publications

(47 citation statements)

References 113 publications

(188 reference statements)

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“…Desmosomes are intercellular junctions that connect intermediate filaments to the cell surface and mediate strong cell-cell adhesion. They are particularly prominent in stratified squamous epithelia and myocardium (55,56). Accordingly, the junctional localization of iASPP is crucial for desmin intermediate filaments to locate at the intercalated discs in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Desmosomes are anchoring junctions that exist in cells that endure physical stress such as cardiac myocytes. The importance of desmosomes in maintaining the homeostasis of the myocardium is underscored by frequent mutations of desmosome components found in human patients and animal models. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a phenotype caused by mutations in desmosomal components in ∼50% of patients, however, the causes in the remaining 50% of patients still remain unknown. A deficiency of inhibitor of apoptosis-stimulating protein of p53 (iASPP), an evolutionarily conserved inhibitor of p53, caused by spontaneous mutation recently has been associated with a lethal autosomal recessive cardiomyopathy in Poll Hereford calves and Wa3 mice. However, the molecular mechanisms that mediate this putative function of iASPP are completely unknown. Here, we show that iASPP is expressed at intercalated discs in human and mouse postmitotic cardiomyocytes. iASPP interacts with desmoplakin and desmin in cardiomyocytes to maintain the integrity of desmosomes and intermediate filament networks in vitro and in vivo. iASPP deficiency specifically induces right ventricular dilatation in mouse embryos at embryonic day 16.5. iASPPdeficient mice with exon 8 deletion (Ppp1r13l Δ8/Δ8 ) die of sudden cardiac death, displaying features of ARVC. Intercalated discs in cardiomyocytes from four of six human ARVC cases show reduced or loss of iASPP. ARVC-derived desmoplakin mutants DSP-1-V30M and DSP-1-S299R exhibit weaker binding to iASPP. These data demonstrate that by interacting with desmoplakin and desmin, iASPP is an important regulator of desmosomal function both in vitro and in vivo. This newly identified property of iASPP may provide new molecular insight into the pathogenesis of ARVC.ARVC | sudden death | desmosome | iASPP | cell-cell junctions

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Section: Discussionmentioning

confidence: 99%

iASPP, a previously unidentified regulator of desmosomes, prevents arrhythmogenic right ventricular cardiomyopathy (ARVC)-induced sudden death

Notari

Sutendra

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The transmembrane desmosomal cadherins interact in the extracellular space to couple the two halves of the desmosome and are linked to the IF network through plakoglobin (PG), plakophilins (PKPs), desmoplakin (DSP) and a number of other proteins (Yin and Green, 2004). The importance of desmosomes for maintenance of the strength and flexibility of these tissues is highlighted by natural and in-vitro-engineered mutations in desmosomal genes, which compromise skin or heart and in some instances both (Bolling and Jonkman, 2009;Chalabreysse et al, 2011;Brooke et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous human mutations in the gene encoding DSP have been identified to date, resulting in a range of clinical phenotypes designated as cardio-cutaneous syndromes. These phenotypes range from non-syndromic skin striate palmoplantar keratoderma (SPPK) through to early lethality due to severe skin blistering and subsequent water loss or sudden death from cardiomyopathy (Bolling and Jonkman, 2009;Brooke et al, 2012). Ablation of DSP in the germline of mice results in lethality at embryonic day 6.5 (E6.5) (Gallicano et al, 1998), and conditional targeting to the epidermis leads to postnatal lethality through skin blistering and extensive water loss (Vasioukhin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

The DSPII splice variant is critical for desmosome-mediated HaCaT keratinocyte adhesion

Cabral

Tattersall

Patel

et al. 2012

Journal of Cell Science

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SummaryDesmosomes are intercellular junctions specialised for strong adhesion that are prominent in the epidermis and heart muscle. Defective desmosomal function due to inherited mutations in the constitutive desmosomal gene desmoplakin (DSP) causes skin or heart disorders and in some instances both. Different mutations have different disease-causing molecular mechanisms as evidenced by the varying phenotypes resulting from mutations affecting different domains of the same protein, but the majority of these mechanisms remain to be determined. Here, we studied two mutations in DSP that lead to different dosages of the two major DSP splice variants, DSPI and DSPII, and compared their molecular mechanisms. One of the mutations results in total DSP haploinsufficiency and is associated with autosomal dominant striate palmoplantar keratoderma (PPK). The other leads to complete absence of DSPI and the minor isoform DSPIa but normal levels of DSPII, and is associated with autosomal recessive epidermolytic PPK, woolly hair and severe arrhythmogenic dilated cardiomyopathy. Using siRNA treatments to mimic these two mutations and additionally a DSPII-specific siRNA, we found striking differences between DSP isoforms with respect to keratinocyte adhesion upon cellular stress with DSPII being the key component in intermediate filament (IF) stability and desmosome-mediated adhesion. In addition, reduction in DSP expression reduced the amount of plakophilin 1, desmocollin (DSC) 2 and DSC3 with DSPI having a greater influence than DSPII on the expression levels of DSC3. These results suggest that the two major DSP splice variants are not completely redundant in function and that DSPII dosage is particularly important for desmosomal adhesion in the skin.

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“…Patients may experience transient pruritic blistering on the trunk or extremities, resulting from acantholysis of the spinous epidermal layers. 74 In contrast to Naxos disease, cardiac involvement is characterized by a primarily left-sided dilated cardiomyopathy. 75 There does appear to be some overlap between the cardiac findings in Naxos disease and Carvajal syndrome, and the outcomes may result from a similar desmosomal defect.…”

Section: Carvajal Syndromementioning

confidence: 99%