Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University.
Circ J. 2013;77(12):2990-6. doi: 10.1253/circj.cj-13-0255. Epub 2013 Oct 1.
Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM.
We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of FHOD3.
The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.
扩张型心肌病（DCM）的特征是左心室腔扩张，伴有心力衰竭表现的收缩功能障碍。已经发现，细胞骨架或肌节蛋白基因的突变会导致 DCM。然而，有家族史的患者中，只有不到一半能发现致病突变，这表明 DCM 应该还有其他疾病基因。含formin 同源结构域 2 的蛋白 3（FHOD3）是一种在心脏中表达的肌节蛋白，在肌原纤维发生过程中对肌节组织起着至关重要的作用。本研究旨在探索 DCM 的一个可能的新的疾病基因。
我们分析了 48 例日本家族性 DCM 患者 FHOD3 的突变情况，在一例成年起病的 DCM 患者中发现了一个错义突变 Tyr1249Asn，该突变预测会改变 3D 结构并损害蛋白功能。功能研究表明，DCM 相关突变显著降低了诱导肌动蛋白动力学依赖性血清反应因子激活的能力，尽管在转染 FHOD3 突变构建体的新生大鼠心肌细胞中并未诱导明显的细胞定位改变。
与 DCM 相关的 FHOD3 变异可能通过干扰肌动蛋白丝组装引起 DCM。
