%0 Journal Article %J CJC Open %D 2022 %T Novel Mutations in β- Gene in Indian Patients With Dilated Cardiomyopathy. %A Rani, Deepa Selvi %A Vijaya Kumar, Archana %A Nallari, Pratibha %A Sampathkumar, Katakam %A Dhandapany, Perundurai S %A Narasimhan, Calambur %A Rathinavel, Andiappan %A Thangaraj, Kumarasamy %X

Background: Heart failure is a hallmark of severe hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Several mutations in the gene lead to hypertrophic cardiomyopathy. Recently, causative mutations in the gene have also been detected in DCM from different populations.

Methods: Here, we sequenced the gene in 137 Indian DCM patients and 167 ethnically matched healthy controls to detect the frequency of mutations and their association.

Results: Our study revealed 27 variations, of which 7 mutations (8.0%) were detected exclusively in Indian DCM patients for the first time. These included 4 missense mutations-Arg723His, Phe510Leu, His358Leu, and Ser384Tyr (2.9%); a frameshift mutation-Asn676_T-del (1.5%); and 2 splice-site mutations (IVS17+2T) T>G and (IVS19-1G) G>A (3.6%). Remarkably, all 4 missense mutations altered evolutionarily conserved amino acids. All 4 missense mutations were predicted to be pathogenic by 2 bioinformatics tools-polymorphism phenotyping v2 (PolyPhen-2) and sorting intolerant from tolerant (SIFT). In addition, the 4 homology models of β-MYH7-p.Leu358, p.Tyr384, p.Leu510, and p.His723-displayed root-mean-square deviations of ∼2.55 Å, ∼1.24 Å, ∼3.36 Å, and ∼3.86 Å, respectively.

Conclusions: In the present study, we detected numerous novel, unique, and rare mutations in the gene exclusively in Indian DCM patients (8.0%). Here, we demonstrated how each mutant (missense) uniquely disrupts a critical network of non-bonding interactions at the mutation site (molecular level) and may contribute to development of dilated cardiomyopathy (DCM). Therefore, our findings may provide insight into the understanding of the molecular bases of disease and into diagnosis along with promoting novel therapeutic strategies (through personalized medicine).

%B CJC Open %V 4 %P 1-11 %8 2022 Jan %G eng %N 1 %R 10.1016/j.cjco.2021.07.020 %0 Journal Article %J NPJ Genom Med %D 2022 %T Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. %A Lesurf, Robert %A Said, Abdelrahman %A Akinrinade, Oyediran %A Breckpot, Jeroen %A Delfosse, Kathleen %A Liu, Ting %A Yao, Roderick %A Persad, Gabrielle %A McKenna, Fintan %A Noche, Ramil R %A Oliveros, Winona %A Mattioli, Kaia %A Shah, Shreya %A Miron, Anastasia %A Yang, Qian %A Meng, Guoliang %A Yue, Michelle Chan Seng %A Sung, Wilson W L %A Thiruvahindrapuram, Bhooma %A Lougheed, Jane %A Oechslin, Erwin %A Mondal, Tapas %A Bergin, Lynn %A Smythe, John %A Jayappa, Shashank %A Rao, Vinay J %A Shenthar, Jayaprakash %A Dhandapany, Perundurai S %A Semsarian, Christopher %A Weintraub, Robert G %A Bagnall, Richard D %A Ingles, Jodie %A Melé, Marta %A Maass, Philipp G %A Ellis, James %A Scherer, Stephen W %A Mital, Seema %X

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

%B NPJ Genom Med %V 7 %P 18 %8 2022 Mar 14 %G eng %N 1 %R 10.1038/s41525-022-00288-y %0 Journal Article %J Sci Adv %D 2021 %T Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin. %A Dhandapany, Perundurai S %A Kang, Soojeong %A Kashyap, Deepak K %A Rajagopal, Raksha %A Sundaresan, Nagalingam R %A Singh, Rajvir %A Thangaraj, Kumarasamy %A Jayaprakash, Shilpa %A Manjunath, Cholenahally N %A Shenthar, Jayaprakash %A Lebeche, Djamel %X

Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 () as risk factors for HCM. Biochemical studies showed that variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal-regulated kinase pathways. A transgenic mouse model expressing an variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that variants can cause HCM and provide new insights into regulation.

%B Sci Adv %V 7 %8 2021 Jan %G eng %N 2 %R 10.1126/sciadv.abb3991 %0 Journal Article %J J Med Genet %D 2021 %T Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy. %A Jain, Pratul Kumar %A Jayappa, Shashank %A Sairam, Thiagarajan %A Mittal, Anupam %A Paul, Sayan %A Rao, Vinay J %A Chittora, Harshil %A Kashyap, Deepak K %A Palakodeti, Dasaradhi %A Thangaraj, Kumarasamy %A Shenthar, Jayaprakash %A Koranchery, Rakesh %A Rajendran, Ranjith %A Alireza, Haghighi %A Mohanan, Kurukkanparampil Sreedharan %A Rathinavel, Andiappan %A Dhandapany, Perundurai S %X

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM.

METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 () gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect.

CONCLUSIONS: Our study demonstrates for the first time that the variants in the gene are associated with HCM, and early detection of the variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of gene variants.

%B J Med Genet %8 2021 Dec 16 %G eng %R 10.1136/jmedgenet-2021-107866 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2020 %T A field-based quantitative analysis of sublethal effects of air pollution on pollinators. %A Thimmegowda, Geetha G %A Mullen, Susan %A Sottilare, Katie %A Sharma, Ankit %A Mohanta, Saptashi Soham %A Brockmann, Axel %A Dhandapany, Perundurai S %A Olsson, Shannon B %X

While the impact of air pollution on human health is well studied, mechanistic impacts of air pollution on wild systems, including those providing essential ecosystem services, are largely unknown, but directly impact our health and well-being. India is the world's largest fruit producer, second most populous country, and contains 9 of the world's 10 most polluted cities. Here, we sampled Giant Asian honey bees, , at locations with varying air pollution levels in Bangalore, India. We observed significant correlations between increased respirable suspended particulate matter (RSPM) deposition and changes in bee survival, flower visitation, heart rate, hemocyte levels, and expression of genes related to lipid metabolism, stress, and immunity. Lab-reared exposed to these same sites also exhibited similar molecular and physiological differences. Our study offers a quantitative analysis on the current impacts of air pollution on insects, and indicates the urgency for more nonhuman studies to accurately assess the effects of pollution on our natural world.

%B Proc Natl Acad Sci U S A %V 117 %P 20653-20661 %8 2020 Aug 25 %G eng %N 34 %R 10.1073/pnas.2009074117 %0 Journal Article %J Biophys Rev %D 2020 %T Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3 variant. %A Arif, Mohammed %A Nabavizadeh, Pooneh %A Song, Taejeong %A Desai, Darshini %A Singh, Rohit %A Bazrafshan, Sholeh %A Kumar, Mohit %A Wang, Yigang %A Gilbert, Richard J %A Dhandapany, Perundurai S %A Becker, Richard C %A Kranias, Evangelia G %A Sadayappan, Sakthivel %X

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3 carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3 variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3 pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.

%B Biophys Rev %V 12 %P 1065-1084 %8 2020 Aug %G eng %N 4 %R 10.1007/s12551-020-00725-1 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2020 %T Reply to Negri et al.: Air pollution and health impacts on bees: Signs of causation. %A Thimmegowda, Geetha G %A Brockmann, Axel %A Dhandapany, Perundurai S %A Olsson, Shannon B %K Air Pollution %K Animals %K Bees %K Health %B Proc Natl Acad Sci U S A %V 117 %P 26578-26579 %8 2020 10 27 %G eng %N 43 %R 10.1073/pnas.2017972117 %0 Journal Article %J Orthop J Sports Med %D 2020 %T VEGFA Promoter Polymorphisms rs699947 and rs35569394 Are Associated With the Risk of Anterior Cruciate Ligament Ruptures Among Indian Athletes: A Cross-sectional Study. %A Shukla, Manish %A Gupta, Rahul %A Pandey, Vivek %A Rochette, Jacques %A Dhandapany, Perundurai S %A Tiwari, Pramod Kumar %A Amrathlal, Rabbind Singh %X

Background: Associations of genetic variants within certain fibril-forming genes have previously been observed with anterior cruciate ligament (ACL) injuries. Evidence suggests a significant role of angiogenesis-associated cytokines in remodeling the ligament fibril matrix after mechanical loading and maintaining structural and functional integrity of the ligament. Functional polymorphisms within the vascular endothelial growth factor A (VEGFA) gene have emerged as plausible candidates owing to their role in the regulation of angiogenic responses.

Hypothesis: VEGFA promoter polymorphisms rs699947 and rs35569394 are associated with ACL injury risk among athletes.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: A total of 90 Indian athletes with radiologically confirmed or surgically proven isolated ACL tears and 76 matched-control athletes were selected for the present cross-sectional genetic association study. Oral mouthwash samples were collected from all the case and control athletes and genotyped for VEGFA rs699947 and rs35569394 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results: The A allele (rs699947) was significantly overrepresented in the ACL group (C vs A allele: odds ratio [OR], 1.68 [95% CI, 1.08-2.60]; = .021) (CC vs CA + AA: OR, 2.69 [95% CI, 1.37-5.26]; = .004). There was a greater frequency of the AA genotype in the ACL group in comparison with the control group (OR, 3.38 [95% CI, 1.23-9.28]; = .016) when only male athletes were compared. Likewise, there was a greater frequency of the I allele (rs35569394) in the ACL group (D vs I allele: OR, 1.64 [95% CI, 1.06-2.55]; = .025) (DD vs ID + II: OR, 2.61 [95% CI, 1.31-5.21]; = .006). The A-I haplotype was overrepresented in the ACL group compared with the control group (OR, 1.68 [95% CI, 1.08-2.60]; χ = 5.320; = .021), and both the polymorphisms were found to be in complete linkage disequilibrium ( = 0.929; logarithm of the odds score = 63.74; D' = 1.0). Female athletes did not show any difference in genotype or allele frequency.

Conclusion: This is the first study to investigate the association of VEGFA promoter polymorphisms in ACL tears among Indian athletes. Increased frequencies of the A allele (rs699947) and I allele (rs35569394) were observed in the ACL group. These results suggest that sequence variants in the VEGF gene are associated with ACL injury risk among athletes. Further research with long-term follow-ups measuring VEGF expression levels during recovery is warranted to establish its role in ACL injuries and healing.

%B Orthop J Sports Med %V 8 %P 2325967120964472 %8 2020 Dec %G eng %N 12 %R 10.1177/2325967120964472 %0 Journal Article %J Sci Rep %D 2019 %T Myocardin ablation in a cardiac-renal rat model. %A Mittal, Anupam %A Rana, Santanu %A Sharma, Rajni %A Kumar, Akhilesh %A Prasad, Rishikesh %A Raut, Satish K %A Sarkar, Sagartirtha %A Saikia, Uma Nahar %A Bahl, Ajay %A Dhandapany, Perundurai S %A Khullar, Madhu %X

Cardiorenal syndrome is defined by primary heart failure conditions influencing or leading to renal injury or dysfunction. Dilated cardiomyopathy (DCM) is a major co-existing form of heart failure (HF) with renal diseases. Myocardin (MYOCD), a cardiac-specific co-activator of serum response factor (SRF), is increased in DCM porcine and patient cardiac tissues and plays a crucial role in the pathophysiology of DCM. Inhibiting the increased MYOCD has shown to be partially rescuing the DCM phenotype in porcine model. However, expression levels of MYOCD in the cardiac tissues of the cardiorenal syndromic patients and the effect of inhibiting MYOCD in a cardiorenal syndrome model remains to be explored. Here, we analyzed the expression levels of MYOCD in the DCM patients with and without renal diseases. We also explored, whether cardiac specific silencing of MYOCD expression could ameliorate the cardiac remodeling and improve cardiac function in a renal artery ligated rat model (RAL). We observed an increase in MYOCD levels in the endomyocardial biopsies of DCM patients associated with renal failure compared to DCM alone. Silencing of MYOCD in RAL rats by a cardiac homing peptide conjugated MYOCD siRNA resulted in attenuation of cardiac hypertrophy, fibrosis and restoration of the left ventricular functions. Our data suggest hyper-activation of MYOCD in the pathogenesis of the cardiorenal failure cases. Also, MYOCD silencing showed beneficial effects by rescuing cardiac hypertrophy, fibrosis, size and function in a cardiorenal rat model.

%B Sci Rep %V 9 %P 5872 %8 2019 Apr 10 %G eng %N 1 %R 10.1038/s41598-019-42009-z %0 Journal Article %J J Cardiovasc Pharmacol Ther %D 2016 %T Melatonin and Human Cardiovascular Disease. %A Pandi-Perumal, Seithikurippu R %A BaHammam, Ahmed S %A Ojike, Nwakile I %A Akinseye, Oluwaseun A %A Kendzerska, Tetyana %A Buttoo, Kenneth %A Dhandapany, Perundurai S %A Brown, Gregory M %A Cardinali, Daniel P %X

The possible therapeutic role of melatonin in the pathophysiology of coronary artery disorder (CAD) is increasingly being recognized. In humans, exogenous melatonin has been shown to decrease nocturnal hypertension, improve systolic and diastolic blood pressure, reduce the pulsatility index in the internal carotid artery, decrease platelet aggregation, and reduce serum catecholamine levels. Low circulating levels of melatonin are reported in individuals with CAD, arterial hypertension, and congestive heart failure. This review assesses current literature on the cardiovascular effects of melatonin in humans. It can be concluded that melatonin deserves to be considered in clinical trials evaluating novel therapeutic interventions for cardiovascular disorders.

%B J Cardiovasc Pharmacol Ther %8 2016 Jul 21 %G eng %R 10.1177/1074248416660622