Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

Abstract

2990ARIMURA T et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp ilated cardiomyopathy (DCM) is a primary cardiac disorder caused by functional abnormalities in cardiomyocytes and is characterized by ventricular chamber dilation with decreased contractility. DCM is a major cause of chronic heart failure and the most common indication for cardiac transplantation. Various etiologies include genetic abnormalities, viral infections, alcohol, mitochondrial dysfunction and metabolic disorders. 1,2 Most of the genetic causes are mutations in genes for sarcomeric proteins, including contractile elements, sarcolemma elements, Z-disc elements, and Z-I region components, which play key roles in the generation and transmission of contractile force. 2 Editorial p 2879Formin homology 2 domain containing 3 (FHOD3) is a member of the formin family. We have previously reported that FHOD3 is a sarcomeric protein that is predominantly expressed in the heart and plays an essential role in the regulation of actin assembly and sarcomeric organization during myofibrillogenesis. 3 FHOD3 contains multiple domains, including GTPase-binding and diaphanous inhibitory domains at the Nterminus, formin homologous 1 (FH1), formin homologous 2 (FH2) and diaphanous autoregulation (DA) domains at the Cterminus. 4 The FH2 domain mediates actin filament nucleation and polymerization, which are accelerated by FH1-mediated Background: 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.

Loss of Sarcomere-associated Formins Disrupts Z-line Organization, but does not Prevent Thin Filament Assembly in Caenorhabditis elegans Muscle

“…Pointing to their clinical relevance, one allele of the human formin gene fhod3 has been associated with increased incidence of hypertrophic cardiomyopathy, while another allele was present in one case of adult onset dilated cardiomyopathy [20,21]. Moreover, expression of FHOD3 and the related FHOD1 formin change differentially during human cardiomyopathies [10,22], suggesting they may play a role in disease progression, or perhaps compensation.…”

Distribution of formins in cardiac muscle: FHOD1 is a component of intercalated discs and costameres

“…These comprise a small number of transmembrane but a larger number of adaptor proteins, which in classical adherens junctions or desmosomes anchor cytoskeletal components to the cytoplasmic face of the plasma membrane. Undoubtedly such future investigations will benefit from the antibodies, which discriminate between FHOD1 and FHOD3, since recent reports showed that mutant forms of FHOD3 are causative for cardiomyopathies in humans (Arimura et al, 2013) and the FHOD1 might participate in cancer cell invasion (Gardberg et al, 2013).…”

Overview of the Muscle Cytoskeleton

“…FHOD3 knockout mice are embryonic lethal mainly due to arrested myocardial development at embryonic day 10.5, indicating that FHOD3 plays a key role in regulating actin dynamics during myofibrillogenesis and is vital for heart development (299). Two different coding variants ( V1151I and Y1249N ) of human FHOD3 gene are associated with increased incidences of familial HCM and DCM, respectively (29,751). Taken together with data from investigations of Lmod2, Tmod1, and CapZ, control of actin dynamics at thin filament ends is critical to maintaining thin filament integrity and proper contractile function [see “The Nebulin family of proteins: a giant regulator of thin filament function” for nebulin’s role in thin filament length regulation].…”