Pleiotropic Phenotypes Associated With PKP2 Variants

Novelli, Valeria; Malkani, K; Cerrone, Marina

doi:10.3389/fcvm.2018.00184

Cited by 26 publications

(18 citation statements)

References 42 publications

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“…The PKP2 gene, encoding plakophilin-2, found in desmosomes within the intercalated discs, links cadherins to intermediate filaments in the cytoskeleton, and has been specifically reviewed previously [108]. This gene was described in one report as being associated with approximately 2.5% of BrS cases in which patients did not harbor mutations in the BrS-related genes SCN5A, CACNA1C, GPD1L, or MOG1 [59].…”

Section: Calcium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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Section: Calcium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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“…Recent studies show that the intercalated disk (ID; including PKP2) not only maintains intercellular coupling, but also modulates transcription pathways fundamental for intracellular Ca 2+ cycling and cardiac rhythm [5,11]. PKP2 variants lead to phenotypes that vary from purely arrhythmogenic to severe mechanical dysfunction and therefore pkp2 alterations are also linked to inherited cardiac conditions as Brugada syndrome and Catecholaminergic polymorphic ventricular tachycardia (CPVT) [12,13,14]. Total knockout of Pkp2 in mice is embryonically lethal, although heterozygous PKP2 deletion in mice does not induce clear phenotypical manifestations and mice live through adulthood.…”

Section: Introductionmentioning

confidence: 99%

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Opbergen

Noorman

Pfenniger

et al. 2019

IJMS

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Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.

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“…To date, the ClinVar database (26) provides a total of 1,005 annotated PKP2 variants (last accessed November 2020); roughly 65% are linked to cardiac conditions, the remaining 35% has been submitted without an associated clinical diagnosis (27). The variant reported here is a frameshift variant (NM_001005242:exon2:c.314del:p.Pro105Leufs * 7) expected to result in either a truncated protein product or haplo-insufficiency through nonsense-mediated mRNA decay.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction

Leone

Palumbo

Saenen

et al. 2021

Front. Cardiovasc. Med.

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Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder with an estimated prevalence between 1:2,000 and 1:5,000 and is characterized by the fibrofatty replacement of cardiomyocytes that predisposes to malignant arrhythmias, heart failure, and sudden cardiac death. The diagnosis is based on the 2010 Task Force Criteria including family history, electrocardiographic traits and arrhythmogenic pattern, specific gene mutations, and structural and/or histological abnormalities. Most ACMs display an autosomal dominant mode of inheritance often with incomplete penetrance and variable expressivity. Genetic screening of patients with ACM identifies pathogenic or likely pathogenic variants, prevalently in genes encoding the cardiac desmosome (PKP2, DSP, DSC2, DSG2, and JUP) or less frequently in non-desmosomal genes (CTNNA3, PLN, TMEM43, RYR2, SCN5A, CDH2, and DES).Methods: In the present study, we performed molecular autopsy in a boy who died suddenly during physical exertion. In addition to post-mortem examination, a DNA sample was analyzed with next-generation sequencing (NGS).Results: The genetic analysis revealed the presence of pathogenic heterozygous c.314del (p.Pro105Leufs*7) frameshift variant in the PKP2 gene. Cascade screening of family members allowed us to identify 12 mutation carriers and to intervene on subjects at risk, many of whom were athletes.Conclusions: Molecular autopsy can establish cardiogenetic diagnosis and allow appropriate preventative measures in high-risk relatives.

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Pleiotropic Phenotypes Associated With PKP2 Variants

Cited by 26 publications

References 42 publications

Brugada Syndrome: Oligogenic or Mendelian Disease?

Brugada Syndrome: Oligogenic or Mendelian Disease?

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Phenotypic Variability of a Pathogenic PKP2 Mutation in an Italian Family Affected by Arrhythmogenic Cardiomyopathy and Juvenile Sudden Death: Considerations From Molecular Autopsy to Sport Restriction

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