G-protein-coupled receptor kinase 5 polymorphism and Takotsubo cardiomyopathy

Novo, Giuseppina; Giambanco, Salvatore; Guglielmo, Marco; Arvigo, Luisa; Sutera, Maria Rita; Giambanco, Francesco; Evola, Salvatore; Vaccarino, Loredana; Bova, M; Lio, Domenico; Assennato, Pasquale; Novo, Salvatore

doi:10.2459/jcm.0000000000000120

Cited by 27 publications

(25 citation statements)

References 34 publications

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“…The lower a SIFT score, the higher the likelihood that a variant is detrimental. We also included the previously reported variant p.Q41L which had been proposed to be beneficial to cardiac function under some conditions, but deleterious to the heart under other 5 6 7 8 . We refrained from analysing the two novel variants as the closest zebrafish homolog of human GRK5 already contains a serine corresponding to position 464 in humans and arginine at position relative to position 549 in humans ( Supplemental Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Several genetic analyses, including GWAS studies, have investigated an impact of GRK5 variations on the cardiovascular system 5 6 7 8 9 . Those studies have concentrated on adult individuals and omitted patients with CHD.…”

Section: Discussionmentioning

confidence: 99%

“…However, its full impact on signalling has not yet been clarified. Moreover, it has also been shown that p.Q41L may predispose to certain cardiac conditions such as Takotsubo cardiomyopathy 7 8 . Similarly, intronic SNPs which have been associated with atrial fibrillation after coronary bypass surgery 9 will require further genetic and biochemical analyses to uncover their apparently clinically relevant but mechanistically unknown function.…”

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confidence: 99%

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The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

Lessel

Tariq

Tena

et al. 2016

Sci Rep

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G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies <10%, and seven very rare polymorphisms with minor allele frequencies <1%, two of which are novel variants. Given their evolutionarily conserved position in zebrafish, in-depth functional characterisation of four variants (p.Q41L, p.G298S, p.R304C and p.T425M) was performed. We tested the effects of these variants on normal subcellular localisation and the ability to desensitise receptor signalling as well as their ability to correct the left-right asymmetry defect upon Grk5l knockdown in zebrafish. While p.Q41L, p.R304C and p.T425M responded normally in the first two aspects, neither p.Q41L nor p.R304C were capable of rescuing the lateralisation phenotype. The fourth variant, p.G298S was identified as a complete loss-of-function variant in all assays and provides insight into the functions of GRK5.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

Lessel

Tariq

Tena

et al. 2016

Sci Rep

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“…19 The aim of these self-limiting processes, called ''bARs desensitization,'' is to protect the heart from prolonged or chronic sympathetic stimulation. 18 Finally, when catecholamine levels come back into normal ranges, b2ARs coupled to Gi proteins switch back to Gs protein coupling, allowing the recovery of myocardial function. 17 Although several authors have tried to investigate the role of these mutations in TS pathophysiology, the results are ambiguous so far.…”

Section: Do Genetic Polymorphisms Play a Significant Role In Ts Onset?mentioning

confidence: 99%

Influence of Genetics and Gender in Takotsubo Syndrome: Unexplored Areas of an Incompletely Understood Disease

LongobardoLuca

ZitoConcetta

Carerj

et al. 2017

Gender and the Genome

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Stress cardiomyopathy, also known as ''Takotsubo syndrome'' (TS), is a complex disease that typically affects postmenopausal women. The pathophysiology is still largely unknown, but evidence of a frequent association between TS and stressful events has evoked the hypothesis of a pathophysiologic role of sympathetic overdrive in the myocardial dysfunction. However, despite several studies, the role gender plays in TS onset remains unclear because stress cardiomyopathy also has been described in young women and in men. Moreover, although several cases of a familial cluster of TS have been reported, no responsible gene mutations or polymorphisms have been clearly identified so far, and neither the modality of transmission or the true impact of genetic background. In this review, we discuss the role of gender in the onset, course, and outcomes of TS and we report the available data about polymorphisms and gene mutations so far investigated, trying to critically analyze the evidence reported in the literature.

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“…39; 42; 45; 46 Until recently, genetic studies were restricted to candidate gene analysis in case series of sporadic SCM patients, 47–51 but these have yielded mainly negative findings. One candidate gene study reported a significant difference in the frequency of a GRK5 polymorphism in cases, 52 but this has not been replicated and past history of single gene association studies suggests it is unlikely to be meaningful. 53 More recently, another candidate gene study has implicated estrogen receptor genes as potential risk factors for SCM.…”

Section: Introductionmentioning

confidence: 99%

Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy

Lacey

Doudney²,

Bridgman

et al. 2017

Preprint

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G-protein-coupled receptor kinase 5 polymorphism and Takotsubo cardiomyopathy

Abstract: In our study, we have found a significant difference in the frequency of GRK5 polymorphism between TTC patients and controls, supporting a genetic predisposition to this cardiac syndrome.

Cited by 27 publications

References 34 publications

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

Influence of Genetics and Gender in Takotsubo Syndrome: Unexplored Areas of an Incompletely Understood Disease

Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy

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