Germline gain-of-function mutations in RAF1 cause Noonan syndrome

Razzaque, Abdur; Nishizawa, Tsutomu; Komoike, Yuta; Yagi, Hisato; Furutani, Michiko; Amo, Ryunosuke; Kamisago, Mitsuhiro; Momma, Kazuo; Katayama, Hiroshi; Nakagawa, Masao; Fujiwara, Yuko; Matsushima, Masaki; Mizuno, Katsumi; Tokuyama, Mika; Hirota, Hamao; Muneuchi, Jun; Higashinakagawa, Toru; Matsuoka, Rumiko

doi:10.1038/ng2078

Cited by 453 publications

(395 citation statements)

References 28 publications

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“…Infants with Costello syndrome are less likely to have severe pulmonary stenosis, or pulmonary stenosis with an atrial septal defect. The lack of complex CHDs currently distinguishes Costello syndrome from Noonan syndrome (PTPN11, RAF1) (and rarely, NF1) in which tetralogy of Fallot or atrioventricular septal defect have been reported occasionally [Lin et al, 2000;Sarkozy et al, 2003;Pandit et al, 2007;Razzaque et al, 2007]. The predominance of valve dysplasia and paucity of cardiac malformation is consistent with the view that these are disorders of dysplasia, rather than malformation.…”

Section: Comparison To Other Rasopathiesmentioning

confidence: 79%

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Lin

Alexander

Colan

et al. 2011

American J of Med Genetics Pt A

114

106

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Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes (“RASopathies”). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non‐progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow‐up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one‐fourth of those with arrhythmia, but is generally self‐limited in the remaining three‐fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated. © 2011 Wiley‐Liss, Inc.

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Section: Comparison To Other Rasopathiesmentioning

confidence: 79%

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Lin

Alexander

Colan

et al. 2011

American J of Med Genetics Pt A

114

106

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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.…”

Section: Resultsmentioning

confidence: 99%

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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“…Mutations in SOS1 were identified in only 10% of our patients with NS and CFC syndrome. Presently unknown genetic causes for mutation-negative NS and related disorders, including recently identified mutations in RAF-1 Razzaque et al 2007), remain to be identified in molecules in the RAS/MAPK cascade.…”

Section: Discussionmentioning

confidence: 99%

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

et al. 2008

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Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also -008-0320-0 been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.123 J Hum Genet (2008) 53:834-841 DOI 10.1007/s10038

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Germline gain-of-function mutations in RAF1 cause Noonan syndrome

Cited by 453 publications

References 28 publications

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

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

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

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