The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
The National Institute for Biotechnology in the Negev, Marcus Campus, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Int J Mol Sci. 2023 Jan 10;24(2):1388. doi: 10.3390/ijms24021388.
Dilated cardiomyopathy (DCM) with left ventricular non-compaction (LVNC) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure, and excessive risk of sudden cardiac death. Using whole-exome sequencing to investigate a possible genetic cause of DCM with LVNC in a consanguineous child, a homozygous nucleotide change c.1532G>A causing p.Arg511His in PHACTR2 was found. The missense change can affect the binding of PHACTR2 to actin by eliminating the hydrogen bonds between them. The amino acid change does not change PHACTR2 localization to the cytoplasm. The patient’s fibroblasts showed a decreased globular to fibrillary actin ratio compared to the control fibroblasts. The re-polymerization of fibrillary actin after treatment with cytochalasin D, which disrupts the actin filaments, was slower in the patient’s fibroblasts. Finally, the patient’s fibroblasts bridged a scar gap slower than the control fibroblasts because of slower and indirect movement. This is the first report of a human variation in this PHACTR family member. The knock-out mouse model presented no significant phenotype. Our data underscore the importance of PHACTR2 in regulating the monomeric actin pool, the kinetics of actin polymerization, and cell movement, emphasizing the importance of actin regulation for the normal function of the human heart.
扩张型心肌病（DCM）合并左心室致密化不全（LVNC）是一种原发性心肌疾病，可导致收缩功能障碍、进行性心力衰竭和心脏性猝死风险增加。采用全外显子组测序技术，对一名近亲婚配的 DCM 合并 LVNC 患儿进行可能的遗传病因学研究，发现 PHACTR2 基因存在 c.1532G>A 纯合核苷酸改变，导致 p.Arg511His 错义突变。该错义突变可通过消除两者之间的氢键，影响 PHACTR2 与肌动蛋白的结合。该氨基酸改变不改变 PHACTR2 向细胞质的定位。与对照组成纤维细胞相比，患者的成纤维细胞小球状肌动蛋白与纤维状肌动蛋白的比值降低。细胞松弛素 D 处理后，纤维状肌动蛋白的重新聚合较慢，这表明肌动蛋白丝被破坏，患者的成纤维细胞比对照组成纤维细胞的肌动蛋白聚合动力学较慢。最后，由于运动较慢且呈间接运动，患者的成纤维细胞跨越疤痕间隙的速度比对照组成纤维细胞慢。这是首次在 PHACTR 家族成员中发现人类变异。敲除小鼠模型没有表现出明显的表型。我们的数据强调了 PHACTR2 对调节单体肌动蛋白池、肌动蛋白聚合动力学和细胞运动的重要性，强调了肌动蛋白调节对人类心脏正常功能的重要性。
