RAF1 mutations in childhood-onset dilated cardiomyopathy

Dhandapany, Perundurai S.; Razzaque, Abdur; Muthusami, Uthiralingam; Kunnoth, Sreejith; Edwards, Janice G.; Mulero‐Navarro, Sonia; Riess, Ilan; Pardo, Sherly; Sheng, Jipo; Rani, Deepa Selvi; Rani, Bindhu; Govindaraj, Periyasamy; Flex, Elisabetta; Yokota, Tomohiro; Furutani, Michiko; Nishizawa, Tsutomu; Nakanishi, Toshio; Robbins, Jeffrey; Limongelli, Giuseppe; Hajjar, Roger J.; Lebeche, Djamel; Bahl, Ajay; Khullar, Madhu; Rathinavel, Andiappan; Sadler, Kirsten C.; Tartaglia, Marco; Matsuoka, Rumiko; Thangaraj, Kumarasamy; Gelb, Bruce D.

doi:10.1038/ng.2963

Cited by 67 publications

(52 citation statements)

References 19 publications

(24 reference statements)

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“…It was reported that gain-of-function mutations in PTPN11 (encoded SHP2) 47,48 and RAF1 49,50 cause Noonan syndrome with hypertrophic cardiomyopathy, a genetic disorder in which the heart muscle becomes thick. In contrast, loss-of-function mutations of RAF1 in humans 51 or genetic deletion of SHP2 28,52 and Raf1 53 in mice cause DCM. As Gab1 is associated with SHP2 and regulates MAPK signaling, it is conceivable that loss of Gab1 could alter MAPK signaling, resulting in DCM.…”

Section: Resultsmentioning

confidence: 95%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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Section: Resultsmentioning

confidence: 95%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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“…Many of the studies on these genes have been carried out in other countries; however, very little data are available in India. Our previous studies on myosin binding protein C ( MyBPC3 ) [7], RAF1 [8], troponin I3 ( TNNI3 ) [9, 10], troponin T2 ( TNNT2 ) [11, 12], and actin ( ACTC ) [14], using the same set of samples (partly/fully), have revealed a few pathogenic mutations [9-16]. The mutations in myosin regulatory ( MYL2) and essential ( MYL3) light chains are reported to be associated with cardiomyopathies, however, there is no study available on these genes in Indian cardiomyopathies, and therefore we studied them.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the etiology of disease due to myosin light-chain genes has remained not understood in Indian cardiomyopathy patients. Previously, we have reported a few mutations and the associations with Indian cardiomyopathies in the following genes: myosin binding protein C ( MyBPC3 ) [7], RAF1 [8], troponin I3 ( TNNI3 ) [9, 10], troponin T2 ( TNNT2 ) [11, 12], tropomyosin ( TPM1) [13], actin ( ACTC ) [14], and cardiac β-myosin heavy chains ( β-MYH7 ), and we also submitted these novel mutations to the dbSNP data bank (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_viewBatch.cgi?sbid = 1062022). In the present study we have screened the myosin regulatory ( MYL2) and essential ( MYL3) light-chain genes to establish their role among Indian cardiomyopathies, using the same set of samples (partly/fully), which were used for the above mutational studies [9-16].…”

Section: Introductionmentioning

confidence: 99%

A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies

et al. 2018

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Background: Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes – 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities. Objectives: Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them. Method: For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India. Results: Our study revealed a total of 10 variations – 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls. Conclusions: MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians.

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“…Recently, the hypothesis was explored that mutations in RAS/mitogen-activated protein kinase pathway genes might be causative for dilated cardiomyopathy [38]. This was premised on the known roles of RAS pathway signaling in myocardial biology and the overlap between genes causing hypertrophic and dilated cardiomyopathies in general.…”

Section: Dilated Cardiomyopathymentioning

confidence: 99%

Cardiomyopathies in Noonan syndrome and the other RASopathies

Gelb

Roberts

Tartaglia

2015

Progress in Pediatric Cardiology

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102

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Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits. Mutations causing these disorders alter proteins relevant for signaling through RAS. Thus, these traits are now collectively called the RASopathies. While the RASopathies have pleiomorphic features, this review will focus on the hypertrophic cardiomyopathy observed in varying percentages of all of these traits. In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy. The pathogeneses for the RASopathy-associated cardiomyopathies are being elucidated, principally using animal models, leading to genotype-specific insights into how signal transduction is perturbed. Based on those findings, small molecule therapies seem possible for RASopathy-associated cardiomyopathies.

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RAF1 mutations in childhood-onset dilated cardiomyopathy

Cited by 67 publications

References 19 publications

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

A Complete Absence of Missense Mutation in Myosin Regulatory and Essential Light Chain Genes of South Indian Hypertrophic and Dilated Cardiomyopathies

Cardiomyopathies in Noonan syndrome and the other RASopathies

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