Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy

Ochoa, Juan Pablo; Sabater-Molina, María; García‐Pinilla, José Manuel; Mogensen, Jens; Restrepo-Córdoba, Alejandra; Palomino-Doza, Julián; Villacorta, Eduardo; Martinez-Moreno, Marina; Ramos-Maqueda, Javier; Zorio, Esther; Peña-Peña, María Luisa; García‐Granja, Pablo Elpidio; Palomares, José F. Rodríguez; Cárdenas-Reyes, Ivonne J.; Torre‐Carpente, María M. De La; Bautista-Pavés, Alicia; Akhtar, Mohammed; Cicerchia, Marcos; Bilbao-Quesada, Raquel; Mogollón-Jiménez, María Victoria; Salazar-Mendiguchía, Joel; Latorre, José M. Mesa; Arnáez, Blanca; Olavarri-Miguel, Ivan; Fuentes‐Cañamero, María Eugenia; Lamounier, Arsonval; Ruiz, José María Pérez; Climent, Vicente; Pérez-Sánchez, Inmaculada; Trujillo-Quintero, Juan Pablo; Lopes, Luís Rocha; Repáraz-Andrade, Alfredo; Marín-Iglesias, Rosario; Rodríguez-Vilela, Alejandro; Sandín‐Fuentes, María; Garrote, José Antonio; Cortel-Fuster, Alejandro; López-Garrido, Miguel A.; Fontalba-Romero, Ana; Ripoll‐Vera, Tomás; Llano-Rivas, Isabel; Fernández-Fernández, Xusto; Isidoro‐García, María; García-Giustiniani, Diego; Barriales‐Villa, Roberto; Ortíz-Genga, Martín; García‐Pavía, Pablo; Elliott, Perry; Gimeno, Juan R.; Monserrat, Lorenzo

doi:10.1016/j.jacc.2018.10.001

Cited by 73 publications

(56 citation statements)

References 22 publications

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“…(formin homology 1), FH2 (formin homology 2) and DAD (diaphanous auto-regulatory domain) domains. 16 In the previous study by Ochoa et al, 16 are the major leading cause of familial HCM. 8,26 In addition, exon 12 plays an essential role in the binding of Fhod3 to cMyBP-C. 26 Through this interaction, FHOD3 localises to the C-zone in the central two-thirds of the A-band (thick myosin filaments) and subsequently plays a role in the maintenance of normal cardiac function.…”

Section: Discussionmentioning

confidence: 90%

“…In the previous study by Ochoa et al, ≥13 FHOD3 mutations were identified as a HCM‐causing mutations, including one non‐frameshift deletion mutation (S527del) and 12 missense mutations (Y528C, R634G, R637W, R637G, R637P, R641S, R644S, N654K, D962N, P1057L, R1386Q and V1576G). Among these, the p.S527del variant was identified in five different European families with strong segregation and, after evaluation of segregation and bioinformatics predictor's analysis, final classification of the variant (p.S527del) was “Pathogenic” in the study by Ochoa et al These 13 HCM‐causing mutations are primarily clustered on two regions of the FHOD3 protein (Figure C). One is a coiled‐coil region in the DID domain, and the other includes residues 527 and 528 in exon 12.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…The FHOD3 protein contains multiple domains, including GBD (GTPase‐binding domain), DID (diaphanous inhibitory domain), FH1 (formin homology 1), FH2 (formin homology 2) and DAD (diaphanous auto‐regulatory domain) domains . In the previous study by Ochoa et al, ≥13 FHOD3 mutations were identified as a HCM‐causing mutations, including one non‐frameshift deletion mutation (S527del) and 12 missense mutations (Y528C, R634G, R637W, R637G, R637P, R641S, R644S, N654K, D962N, P1057L, R1386Q and V1576G). Among these, the p.S527del variant was identified in five different European families with strong segregation and, after evaluation of segregation and bioinformatics predictor's analysis, final classification of the variant (p.S527del) was “Pathogenic” in the study by Ochoa et al These 13 HCM‐causing mutations are primarily clustered on two regions of the FHOD3 protein (Figure C).…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] Studies in FHOD3-knockout mice established that FHOD3 plays a role in the maintenance of normal cardiac function of the perinatal and adult heart. 25 In 2018, Ochoa et al 16 first reported that FHOD3 was considered a novel genetic cause of HCM in a large scale European population study. They also reported that mutation of FHOD3 results in a more benign clinical course, which is consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

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Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

Huang

Tian

Wei

et al. 2020

The Journal of Gene Medicine

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Background Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiac disease and is characterised by unexplained ventricular myocardial hypertrophy. HCM is highly heterogeneous and is primarily caused by the mutation of genes encoding sarcomere proteins. As a result of its genetic basis, we investigated the underlying cause of HCM in a Chinese family by whole‐exome sequencing. Methods Whole‐exome sequencing was performed for seven clinically diagnosed HCM family members and the resulting single nucleotide variants associated with cardiac hypertrophy or heart development were analysed by a polymerase chain reaction and Sanger sequencing. Results A non‐frameshift deletion mutation (p.S527del) of Formin Homology 2 Domain Containing 3 (FHOD3) was detected in all of the affected family members and was absent in all unaffected members, with the exception of one young member. Moreover, three single nucleotide variants associated with heart development and morphogenesis were identified in the proband but were absent in the other affected subjects. Conclusions This is the first HCM family case of FHOD3 (p.S527del) variation in Asia. Additionally, RNF207 (p.Q268P), CCM2 (p. E233K) and SGCZ (p.Q134X) may be related to the clinical heterogeneity of the family. The present study could enable the provision of genetic counseling for this family and provide a basis for future genetic and functional studies.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

Huang

Tian

Wei

et al. 2020

The Journal of Gene Medicine

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Genetic Testing in High-risk Spontaneous Coronary Artery Dissection—Searching for Clinical Utility Among Background Genetic Noise

Giudicessi

Hayes

2022

JAMA Cardiol

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FHOD‐1 is the only formin in Caenorhabditis elegans that promotes striated muscle growth and Z‐line organization in a cell autonomous manner

et al. 2020

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The striated body wall muscles of Caenorhabditis elegans are a simple model for sarcomere assembly. Previously, we observed deletion mutants for two formin genes, fhod-1 and cyk-1, develop thin muscles with abnormal dense bodies (the sarcomere Z-line analogs). However, this work left in question whether these formins work in a muscle cell autonomous manner, particularly since cyk-1(Δ) deletion has pleiotropic effects on development. Using a fast acting temperature-sensitive cyk-1(ts) mutant, we show here that neither postembryonic loss nor acute loss of CYK-1 during embryonic sarcomerogenesis cause lasting muscle defects. Furthermore, mosaic expression of CYK-1 in cyk-1(Δ) mutants is unable to rescue muscle defects in a cell autonomous manner, suggesting muscle phenotypes caused by cyk-1(Δ) are likely indirect. Conversely, mosaic expression of FHOD-1 in fhod-1(Δ) mutants promotes muscle cell growth and proper dense body organization in a muscle cell autonomous manner. As we observe no effect of loss of any other formin on muscle development, we conclude FHOD-1 is the only worm formin that directly promotes striated muscle development, and the effects on formin loss in C. elegans are surprisingly modest compared to other systems.

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Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy

Cited by 73 publications

References 22 publications

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy

Genetic Testing in High-risk Spontaneous Coronary Artery Dissection—Searching for Clinical Utility Among Background Genetic Noise

FHOD‐1 is the only formin in Caenorhabditis elegans that promotes striated muscle growth and Z‐line organization in a cell autonomous manner

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