ABSTRACT
OBJECTIVE: Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. While sarcomeric gene mutations explain many HCM cases, the genetic basis of about half of HCM cases remains elusive. Here we aimed to identify the gene causing HCM in a non-consanguineous Saudi Arabian family with affected family members and a history of sudden death. The impact of the identified mutation on protein structure and potential drug targets were evaluated in silico. MATERIALS AND METHODS: Triplets (two HCM subjects and one patent ductus arteriosus (PDA) case) and unaffected parents were screened by targeted next-generation sequencing (NGS) for 181 candidate cardiomyopathy genes. In silico structural and functional analyses, including protein modeling, structure prediction, drug screening, drug binding, and dynamic simulations were performed to explore the potential pathogenicity of the variant and to identify candidate drugs. RESULTS: A homozygous missense mutation in exon 1 of TMP1 (assembly GRCh37-chr15: 63340781; G>A) was identified in the triplets [two HCM and one patent ductus arteriosus (PDA)] that substituted glycine for arginine at codon 3 (p.Gly3Arg). The parents were heterozygous for the variant. The mutation was predicted to cause a significant and deleterious change in the TPM1 protein structure that slightly affected drug binding, stability, and conformation. In addition, we identified several putative TPM1-targeting drugs through structure-based in silico screening. CONCLUSIONS: TPM1 mutations are a common cause of HCM and other congenital heart defects. To date, TPM1 has not been associated with isolated PDA; to our knowledge, this is the first report of the homozygous missense variation p.Gly3Arg in TPM1 associated with familial autosomal recessive pediatric HCM and PDA. The identified candidate TPM1 inhibitors warrant further prospective investigation.
Subject(s)
Cardiomyopathy, Dilated/genetics , Ductus Arteriosus, Patent/genetics , Mutation, Missense , Triplets/genetics , Tropomyosin/genetics , Adult , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/drug therapy , Cardiomyopathy, Dilated/metabolism , Child , DNA Mutational Analysis , Ductus Arteriosus, Patent/diagnosis , Ductus Arteriosus, Patent/drug therapy , Ductus Arteriosus, Patent/metabolism , Female , Genetic Predisposition to Disease , Heredity , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Male , Molecular Docking Simulation , Molecular Dynamics Simulation , Pedigree , Phenotype , Protein Binding , Protein Conformation , Protein Stability , Tropomyosin/metabolism , Young AdultABSTRACT
OBJECTIVE: Rheumatic heart disease (RHD) is a serious complication of rheumatic fever (RF). Plasma homocysteine (Hcy) levels are increased in RHD patients. MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and plays a vital role in Hcy metabolism. We hypothesize that the MTHFR C677T polymorphism is associated with a risk of RHD. PATIENTS AND METHODS: Eighty-six patients with RHD and 130 matched controls without a history of RHD were eligible for the study. The diagnosis of RHD was made according to modified Jones' criteria and echocardiography. Using echocardiography, RHD patients were further divided into mitral valve lesion (MVL) and combined valve lesion (CVL) groups. MTHFR C677T polymorphisms were genotyped by DNA sequencing. The chi-squared test was used to evaluate differences in genotypes. RESULTS: Control genotypes were in Hardy-Weinberg equilibrium. The C677T homozygous genotype (OR = 4.09; 95% CIs 1.16-14.44; p = 0.020) and recessive model (TT vs. CC+CT; OR = 4.05; 95% CIs 1.17-14.04; p = 0.019) were significantly associated with MVL RHD. CONCLUSIONS: This is the first study to investigate the association between the MTHFR C677T polymorphism and risk of RHD. The MTHFR C677T polymorphism is associated with RHD in patients with MVLs, perhaps via an Hcy-mediated cytokine effect.
