Germline-Activating RRAS2 Mutations Cause Noonan Syndrome

Niihori, Tetsuya; Nagai, Koki; Fujita, Atsushi; Ohashi, Hirofumi; Okamoto, Nobuhiko; Okada, Satoshi; Harada, Atsuko; Kihara, Hirotaka; Arbogast, Thomas; Funayama, Ryo; Shirota, Matsuyuki; Nakayama, Keiko; Abe, Taiki; Inoue, Shinichi; Tsai, I‐Chun; Matsumoto, Naomichi; Davis, Erica E.; Katsanis, Nicholas; Aoki, Yoko

doi:10.1016/j.ajhg.2019.04.014

Cited by 42 publications

(53 citation statements)

References 32 publications

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“…Consistently, it was originally demonstrated that RRAS2 proteins containing amino acid substitutions analogous to those with oncogenic role in HRAS, KRAS, and NRAS have transforming properties comparable to the strong transforming activity of RAS oncoproteins and similarly promote constitutive activation of the MAPK cascade. 55 Our findings, which are in line with the data presented in an accompanying report by Niihori et al published in this issue, 56 further extend these observations by demonstrating the clinical relevance of a narrow spectrum of germline pathogenic variants in RRAS2 as the event underlying a small fraction of NS cases via upregulation of MAPK signaling. Further studies are required to more accurately define the precise mechanisms and circuits linking upregulated RRAS2 function and RAS-MAPK signaling dysregulation.…”

supporting

confidence: 91%

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

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Flex

Krumbach

et al. 2019

The American Journal of Human Genetics

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Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

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supporting

confidence: 91%

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Capri

Flex

Krumbach

et al. 2019

The American Journal of Human Genetics

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“…In the presence of a growth stimulus, this blocking is uninhibited, allowing RAS to bind to SOS1, leading to the activation of down-stream singnaling [27,28]. Despite extensive efforts utilizing single gene, targeted panel, and whole exome sequencing in order to discover reponsible genes of RASopathies, around 20% of patients with RASopathies remain genetically undiagnosed [4,[8][9][10][11][12], as in our studies [13,24] (Fig. 1).…”

Section: Genetic Heterogeneity and Molecular Genetics Of Noonan Syndrsupporting

confidence: 56%

“…Understanding of correlations between phenotypes and genotypes is able to make genotype-based surveillance and management possible. For instances, the PTPN11 mutations are commonly associated with pulmonary stenosis, pectus deformity easy bruising and hematological malignancies [5,29], while hypertrophic cardiomyopathy is often correlated with RAF1 and RIT1 mutations [8,13,22]. In Korean NS patients, pulmonary stenosis is prevalent in SOS1 mutation carrying patients (~80%), as in other reports (~70%) [24,30].…”

Section: Genotype-phenotype Correlationmentioning

confidence: 72%

“…The SHOC2 mutation was reported in NS-like patients with loose anagen hair [17]. So far, the causative genes are still elusive in 20% of patients with NS [7,8,10,12]. The BRAF (~50%), MEK1 and MEK2 mutations are found in 60-80% of CFC patients [4,15,[18][19][20][21].…”

Section: Genetic Heterogeneity and Molecular Genetics Of Noonan Syndrmentioning

confidence: 99%

“…During past 20 years, many genes responsible for NS are discovered since Tartaglia et al [5] identified the heterozygous mutation in PTPN11 in 2001. As of 2019, more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2) were known to cause NS and its related disorders [6][7][8]. Since the consequences of genetic defect of these genes are the gain of function in the rat sarcoma viral oncogene (RAS) /mitogen-activated protein kinase (MAPK) pathway, Noonan syndrome and its related disorders (LEOPARD, CFC, CSs, and neurofibromatosis type I) are named as RASopathies [7,9].…”

Section: Introductionmentioning

confidence: 99%

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Noonan syndrome and RASopathies: Clinical features, diagnosis and management

Lee

Yoo

2019

J Genet Med

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Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. Clinical presentations are similar, featured with typical facial features, short stature, intellectual disability, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (

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Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant

Pires

Bordim

Maciel

et al. 2021

American J of Med Genetics Pt A

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Noonan syndrome (NS) is a Mendelian phenotype, member of a group of disorders sharing neurocardiofaciocutaneous involvement, known as RASopathies, caused by germline variants in genes coding for components of the RAS/MAPK signaling pathway. Recently, a novel gene of the RAS family (MRAS) was reported to be associated with NS in five children, all of them presenting, among the cardinal features of NS,

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Germline-Activating RRAS2 Mutations Cause Noonan Syndrome

Cited by 42 publications

References 32 publications

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Noonan syndrome and RASopathies: Clinical features, diagnosis and management

Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant

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