TY - JOUR T1 - Novel Mutations in β- Gene in Indian Patients With Dilated Cardiomyopathy. JF - CJC Open Y1 - 2022 A1 - Rani, Deepa Selvi A1 - Vijaya Kumar, Archana A1 - Nallari, Pratibha A1 - Sampathkumar, Katakam A1 - Dhandapany, Perundurai S A1 - Narasimhan, Calambur A1 - Rathinavel, Andiappan A1 - Thangaraj, Kumarasamy AB -

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).

VL - 4 IS - 1 ER - TY - JOUR T1 - Adiponectin receptor 1 variants contribute to hypertrophic cardiomyopathy that can be reversed by rapamycin. JF - Sci Adv Y1 - 2021 A1 - Dhandapany, Perundurai S A1 - Kang, Soojeong A1 - Kashyap, Deepak K A1 - Rajagopal, Raksha A1 - Sundaresan, Nagalingam R A1 - Singh, Rajvir A1 - Thangaraj, Kumarasamy A1 - Jayaprakash, Shilpa A1 - Manjunath, Cholenahally N A1 - Shenthar, Jayaprakash A1 - Lebeche, Djamel AB -

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.

VL - 7 IS - 2 ER - TY - JOUR T1 - Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy. JF - J Med Genet Y1 - 2021 A1 - Jain, Pratul Kumar A1 - Jayappa, Shashank A1 - Sairam, Thiagarajan A1 - Mittal, Anupam A1 - Paul, Sayan A1 - Rao, Vinay J A1 - Chittora, Harshil A1 - Kashyap, Deepak K A1 - Palakodeti, Dasaradhi A1 - Thangaraj, Kumarasamy A1 - Shenthar, Jayaprakash A1 - Koranchery, Rakesh A1 - Rajendran, Ranjith A1 - Alireza, Haghighi A1 - Mohanan, Kurukkanparampil Sreedharan A1 - Rathinavel, Andiappan A1 - Dhandapany, Perundurai S AB -

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.

ER - TY - JOUR T1 - Mechanistic heterogeneity in contractile properties of α-tropomyosin (TPM1) mutants associated with inherited cardiomyopathies. JF - J Biol Chem Y1 - 2015 A1 - Gupte, Tejas M A1 - Haque, Farah A1 - Gangadharan, Binnu A1 - Sunitha, Margaret S A1 - Mukherjee, Souhrid A1 - Anandhan, Swetha A1 - Rani, Deepa Selvi A1 - Mukundan, Namita A1 - Jambekar, Amruta A1 - Thangaraj, Kumarasamy A1 - Sowdhamini, Ramanathan A1 - Sommese, Ruth F A1 - Nag, Suman A1 - Spudich, James A A1 - Mercer, John A KW - Actins KW - Adenosine Triphosphatases KW - Calcium KW - Cardiomyopathies KW - Humans KW - Models, Molecular KW - Myosins KW - Point Mutation KW - Protein Stability KW - Tropomyosin AB -

The most frequent known causes of primary cardiomyopathies are mutations in the genes encoding sarcomeric proteins. Among those are 30 single-residue mutations in TPM1, the gene encoding α-tropomyosin. We examined seven mutant tropomyosins, E62Q, D84N, I172T, L185R, S215L, D230N, and M281T, that were chosen based on their clinical severity and locations along the molecule. The goal of our study was to determine how the biochemical characteristics of each of these mutant proteins are altered, which in turn could provide a structural rationale for treatment of the cardiomyopathies they produce. Measurements of Ca(2+) sensitivity of human β-cardiac myosin ATPase activity are consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca(2+) activation, and dilated cardiomyopathies are hyposensitive. We also report correlations between ATPase activity at maximum Ca(2+) concentrations and conformational changes in TnC measured using a fluorescent probe, which provide evidence that different substitutions perturb the structure of the regulatory complex in different ways. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally, we examined a computationally designed mutant, E181K, that is hypersensitive, confirming predictions derived from in silico structural analysis.

VL - 290 IS - 11 ER -