Positional mapping ofPRKD1,NRP1andPRDM1as novel candidate disease genes in truncus arteriosus

Shaheen, Ranad; Hashem, Amal Al; Alghamdi, Mohammed H.; Seidahmad, Mohammed Zain; Wakil, Salma M.; Dagriri, Khalid; Keavney, Bernard; Goodship, Judith A.; Alyousif, Saad; Alhabshan, Fahad; Al-Hussein, Khalid; Almoisheer, Agaadir; Ibrahim, Niema; Alkuraya, Fowzan S.

doi:10.1136/jmedgenet-2015-102992

Cited by 34 publications

(25 citation statements)

References 41 publications

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“…Unraveling these complex interactions at the molecular and cellular level in mouse models will inform our interpretation of human genetic data obtained from patients with congenital heart defects, where a heterozygous single gene mutation is rarely found to be causative. In support of the idea that defective NRP1 signaling contributes to human congenital heart disease, a recent GWAS study uncovered a nucleotide polymorphism in the NRP1 sequence that was associated with tetralogy of Fallot, while another study identified a homozygous splice mutation that ablates NRP1 exon 3 in a patient with CAT and is predicted to disrupt the semaphorin-binding domain of NRP1 (74,75).…”

Section: Discussionmentioning

confidence: 98%

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Plein¹,

Calmont²,

Fantin³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 98%

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Plein¹,

Calmont²,

Fantin³

et al. 2015

J. Clin. Invest.

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“…PKD signaling has already been implicated in the regulation of energy substrate utilization and insulin secretion. Intriguingly the PRKD1 gene locus has also been associated with increased body mass index (Speliotes et al, 2010; Comuzzie et al, 2012; Graff et al, 2013; Shaheen et al, 2015; Sifrim et al, 2016). Graff et al (2013) further found a stronger impact during adolescence than in older adults which could reflect PKD expression decline in adulthood (as shown in rodent hearts; Haworth et al, 2000; Vega et al, 2004; Guo et al, 2011).…”

Section: Metabolic Stress-dependent Pkd Signalingmentioning

confidence: 99%

“…In vivo , cardiac-specific expression of constitutively active PKD1 caused pronounced dilated cardiomyopathy; and PKD expression and activity is increased in failing mouse, rat, rabbit and human myocardium vs. non-failing (Harrison et al, 2006; Bossuyt et al, 2008; Taglieri et al, 2014). Genetic studies including genome wide association studies also linked mutations in the PRKD1 gene to syndromic congenital heart defects and body mass index (an established risk factor for cardiovascular disease; Speliotes et al, 2010; Comuzzie et al, 2012; Graff et al, 2013; Shaheen et al, 2015; Sifrim et al, 2016). In loss-of-function studies, cardiac-specific PKD1 knockout mice (cKO) proved remarkably resistant to cardiac hypertrophy and fibrosis in response to pressure overload or chronic administration of both isoproterenol and angiotensin (Fielitz et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Emergency Spatiotemporal Shift: The Response of Protein Kinase D to Stress Signals in the Cardiovascular System

Wood

Bossuyt

2017

Front. Pharmacol.

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Protein Kinase D isoforms (PKD 1-3) are key mediators of neurohormonal, oxidative, and metabolic stress signals. PKDs impact a wide variety of signaling pathways and cellular functions including actin dynamics, vesicle trafficking, cell motility, survival, contractility, energy substrate utilization, and gene transcription. PKD activity is also increasingly linked to cancer, immune regulation, pain modulation, memory, angiogenesis, and cardiovascular disease. This increasing complexity and diversity of PKD function, highlights the importance of tight spatiotemporal control of the kinase via protein–protein interactions, post-translational modifications or targeting via scaffolding proteins. In this review, we focus on the spatiotemporal regulation and effects of PKD signaling in response to neurohormonal, oxidant and metabolic signals that have implications for myocardial disease. Precise targeting of these mechanisms will be crucial in the design of PKD-based therapeutic strategies.

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“…Multiple studies show an increased burden of rare CNV in patients affected with ToF compared with controls, and several recurrent loci have been reported to be pathogenic for ToF, the most notable being the deletion responsible for 22q11.2 deletion syndrome. 6–12 Nevertheless, Chinese studies are lacking.…”

Section: Introductionmentioning

confidence: 99%

De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients

et al. 2016

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Conotruncal heart anomalies (CTDs) are particularly prevalent congenital heart diseases (CHD) in Hong Kong. We surveyed large (>500 kb), rare (<1% frequency in controls) copy-number variations (CNVs) in Chinese patients with CTDs to identify potentially disease-causing variations. Adults who tested negative for 22q11.2 deletions were recruited from the adult CHD clinic in Hong Kong. Using a stringent calling criteria, high-confidence CNV calls were obtained, and a large control set comprising 3,987 Caucasian and 1,945 Singapore Chinese subjects was used to identify rare CNVs. Ten large rare CNVs were identified, and 3 in 108 individuals were confirmed to harbour de novo CNVs. All three patients were syndromic with a more complex phenotype, and each of these CNVs overlapped regions likely to be important in CHD. One was a 611 kb deletion at 17p13.3, telomeric to the Miller–Dieker syndrome (MDS) critical region, overlapping the NXN gene. Another was a 5 Mb deletion at 13q33.3, within a previously described critical region for CHD. A third CNV, previously unreported, was a large duplication at 2q22.3 overlapping the ZEB2 gene. The commonly reported 1q21.1 recurrent duplication was not observed in this Chinese cohort. We provide detailed phenotypic and genotypic descriptions of large rare genic CNVs that may represent CHD loci in the East Asian population. Larger samples of Chinese origin will be required to determine whether the genome-wide distribution differs from that found in predominantly European CHD cohorts.

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Positional mapping ofPRKD1,NRP1andPRDM1as novel candidate disease genes in truncus arteriosus

Cited by 34 publications

References 41 publications

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Emergency Spatiotemporal Shift: The Response of Protein Kinase D to Stress Signals in the Cardiovascular System

De novo large rare copy-number variations contribute to conotruncal heart disease in Chinese patients

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