Cardiogenetics Unit, Pediatrics Department, College of Medicine, Taibah University, Al-Madinah, Kingdom of Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2020 Jul;24(14):7732-7744. doi: 10.26355/eurrev_202007_22299.
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.
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.
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.
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.
家族性肥厚型心肌病（HCM）是最常见的遗传性心脏病。虽然肌节基因突变解释了许多 HCM 病例，但仍有大约一半 HCM 病例的遗传基础尚未确定。本研究旨在鉴定一个非近亲沙特阿拉伯家系中导致 HCM 的基因，该家系有受影响的家族成员和猝死史。通过计算机模拟评估所鉴定突变对蛋白质结构和潜在药物靶点的影响。
对三胞胎（两名 HCM 患者和一名动脉导管未闭（PDA）患者）和未受影响的父母进行靶向下一代测序（NGS），以筛选 181 种候选心肌病基因。进行了计算机结构和功能分析，包括蛋白质建模、结构预测、药物筛选、药物结合和动态模拟，以探讨变异的潜在致病性并确定候选药物。
在三胞胎（两名 HCM 患者和一名动脉导管未闭（PDA）患者）中发现 TMP1 外显子 1 中的纯合错义突变（组装 GRCh37-chr15：63340781；G>A），导致密码子 3 处甘氨酸替换为精氨酸（p.Gly3Arg）。父母为该变体的杂合子。该突变预计会导致 TPM1 蛋白结构发生显著且有害的变化，略微影响药物结合、稳定性和构象。此外，我们通过基于结构的计算机筛选鉴定了几种潜在的 TPM1 靶向药物。
TPM1 突变是 HCM 和其他先天性心脏缺陷的常见原因。迄今为止，TPM1 尚未与孤立的 PDA 相关；据我们所知，这是第一个报道 TPM1 中的纯合错义变异 p.Gly3Arg 与家族性常染色体隐性儿科 HCM 和 PDA 相关的报告。所鉴定的候选 TPM1 抑制剂值得进一步前瞻性研究。
