Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis

Kano, Masashi; Takeya, Ryu; Abe, Takaya; Kitajima, Naoyuki; Nishida, Motohiro; Tominaga, Ryuji; Kurose, Hitoshi; Sumimoto, Hideki

doi:10.1242/bio.20121370

Cited by 68 publications

(111 citation statements)

References 39 publications

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“…Cardiac FHOD3 plays a crucial role in the sarcomere organization of cardiomyocytes, is essential for heart myofibrillogenesis [28] and is required for the maintenance of the contractile structures in heart muscle. A cardiac isoform of FHOD3 is targeted to thin actin filaments via phosphorylation of tyrosine residue preventing autophagy dependent degradation [29].…”

Section: Discussionmentioning

confidence: 99%

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Esslinger

Garnier

Korniat

et al. 2018

Archives of Cardiovascular Diseases Supplements

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AimsDilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Data Availability Statement: Genotyping data and phenotypes of the patients and controls are not available due to signed consent and ethical limitations. These data will not be available upon request. However, the summary statistics for association of all SNPs are included as supplementary files S5 and S6 Tables. Funding:The study was supported by the Leducq Transatlantic Network: "Genomic, epigenomic and systems dissection of mechanisms underlying Methods and results116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCMassociated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. ConclusionWe identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Esslinger

Garnier

Korniat

et al. 2018

Archives of Cardiovascular Diseases Supplements

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“…8, 9 We have demonstrated that Fhod3 knockout mice display abnormal maturation of muscle fibers in the heart, resulting in embryonic lethality with ventricular hypokinesia. 10 In addition, transgenic mice expressing a mutant FHOD3 protein with Ile1127Ala (I1127A) substitution in the FH2 domain, which is defective in actin-assembling activity, exhibits phenotypic changes similar to DCM. 10 Moreover, it has recently been reported that knockdown of fhos, the fly homolog of mammalian FHOD, in Drosophila develops heart failure resembling to DCM.…”

Section: Srf Reporter Gene Activitymentioning

confidence: 99%

“…10 In addition, transgenic mice expressing a mutant FHOD3 protein with Ile1127Ala (I1127A) substitution in the FH2 domain, which is defective in actin-assembling activity, exhibits phenotypic changes similar to DCM. 10 Moreover, it has recently been reported that knockdown of fhos, the fly homolog of mammalian FHOD, in Drosophila develops heart failure resembling to DCM. 11 However, there is no report on FHOD3 mutation in patients with DCM.…”

Section: Srf Reporter Gene Activitymentioning

confidence: 99%

“…An important role of FHOD3 in cardiac function is supported by the observation that transgenic mice overexpressing the murine I1127A-FHOD3 protein, which is defective in in-vivo actin-assembling activity, exhibit dilation of the cardiac chambers. 10 In addition, it has been recently reported that a common polymorphism, V1151I (rs2303510), of FHOD3 is associated with hypertrophic cardiomyopathy (HCM), and expression of FHOD3 is increased in the HCM heart at both the mRNA and protein level, 11 albeit that HCM is characterized by cardiac hypertrophy with diastolic dysfunction, which is different from DCM. 13 Moreover, we previously reported that FHOD3 participates in sarcomere organization and is essential for myofibrillogenesis at an early stage of heart development.…”

Section: Functional Relevance Of the Fhod3 Mutationmentioning

confidence: 99%

“…13 Moreover, we previously reported that FHOD3 participates in sarcomere organization and is essential for myofibrillogenesis at an early stage of heart development. 10 In the transition from nascent to mature myofibrils during the myofibrillogenesis, the sarcomere structure required for muscle contraction is organized and stabilized by the increased number of myofibrillar proteins. However, the turnover and re-organization mechanisms of actin assembly by FHOD3 and its contribution to sarcomere structure as well as to the muscle contractility in the adult heart are largely unknown.…”

Section: Functional Relevance Of the Fhod3 Mutationmentioning

confidence: 99%

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

Arimura

Takeya

Ishikawa

et al. 2013

Circ J

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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.

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Regulation of Structure and Function of Sarcomeric Actin Filaments in Striated Muscle of the Nematode Caenorhabditis elegans

Ono

2014

The Anatomical Record

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The nematode Caenorhabditis elegans has been used as a valuable system to study structure and function of striated muscle. The body wall muscle of C. elegans is obliquely striated muscle with highly organized sarcomeric assembly of actin, myosin, and other accessary proteins. Genetic and molecular biological studies in C. elegans have identified a number of genes encoding structural and regulatory components for the muscle contractile apparatuses, and many of them have counterparts in mammalian cardiac and skeletal muscles or striated muscles in other invertebrates. Applicability of genetics, cell biology, and biochemistry has made C. elegans an excellent system to study mechanisms of muscle contractility and assembly and maintenance of myofibrils. This review focuses on the regulatory mechanisms of structure and function of actin filaments in the C. elegans body wall muscle. Sarcomeric actin filaments in C. elegans muscle are associated with the troponin-tropomyosin system that regulates the actin-myosin interaction. Proteins that bind to the side and ends of actin filaments support ordered assembly of thin filaments. Furthermore, regulators of actin dynamics play important roles in initial assembly, growth, and maintenance of sarcomeres. The knowledge acquired in C. elegans can serve as bases to understand the basic mechanisms of muscle structure and function.

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Mammalian formin Fhod3 plays an essential role in cardiogenesis by organizing myofibrillogenesis

Cited by 68 publications

References 39 publications

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

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

Regulation of Structure and Function of Sarcomeric Actin Filaments in Striated Muscle of the Nematode Caenorhabditis elegans

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