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

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.

%B J Biol Chem %V 290 %P 7003-15 %8 2015 Mar 13 %G eng %N 11 %R 10.1074/jbc.M114.596676