%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 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