Germline<i>RRAS2</i>mutations are not associated with Noonan syndrome

Ceremsak, John J; Yu, Ariel; Esquivel, Emilio; Lißewski, Christina; Zenker, Martin; Loh, Mignon L.; Stieglitz, Elliot

doi:10.1136/jmedgenet-2016-103889

Cited by 7 publications

(5 citation statements)

References 7 publications

(9 reference statements)

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“…RRAS, RRAS2, and MRAS are the three members of the RRAS subfamily considered as the closest relatives of the “classic” RAS proteins, HRAS, KRAS, and NRAS (Weber & Carroll, 2021 ). While the physiological role of these GTPases is still poorly understood, the identification of pathogenic variants in both cancer and developmental disorders document their important function on cellular processes (Flex et al, 2014 ; Ceremsak et al, 2016 ; Higgins et al, 2017 ; Capri et al, 2019 ; Niihori et al, 2019 ; Motta, Sagi‐Dain, et al, 2020 ). The functional motifs and domains of these six GTPases are relatively conserved, including the post‐translational processing at the C‐terminus, which however involves different lipidation events in individual proteins (Weber & Carroll, 2021 ).…”

Section: The Last 5 Years: Novel Rasopathy Genes N...mentioning

confidence: 99%

“…These somatic mutations are missense and affect residues homologous to the cancer‐associated ones mutated in HRAS, KRAS and NRAS. Of note, the p.Gln72Leu change (equivalent to p.Gln61Leu in “classical” RAS proteins) was identified as driver event in isolated JMML (Ceremsak et al, 2016 ). Using an inducible RRAS2 Q72L knock‐in mouse model, it was recently shown that this mutation triggers rapid development of a wide spectrum of tumors having limited overlap with those originated by oncogenic mutations in “classical” RAS genes, and showing tissue‐specific pharmacological vulnerabilities, which however not included inhibition of MAPK signaling (Fernandez‐Pisonero et al, 2022 ).…”

Section: The Last 5 Years: Novel Rasopathy Genes N...mentioning

confidence: 99%

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The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Tartaglia

Aoki

Gelb

2022

American J of Med Genetics Pt C

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Enhanced signaling through RAS and the mitogen-associated protein kinase (MAPK) cascade underlies the RASopathies, a family of clinically related disorders affecting development and growth. In RASopathies, increased RAS-MAPK signaling can result from the upregulated activity of various RAS GTPases, enhanced function of proteins positively controlling RAS function or favoring the efficient transmission of RAS signaling to downstream transducers, functional upregulation of RAS effectors belonging to the MAPK cascade, or inefficient signaling switch-off operated by feedback mechanisms acting at different levels. The massive effort in RASopathy gene discovery performed in the last 20 years has identified more than 20 genes implicated in these disorders. It has also facilitated the characterization of several molecular acti-vating mechanisms that had remained unappreciated due to their minor impact in oncogenesis. Here, we provide an overview on the discoveries collected during the last 5 years that have delivered unexpected insights (e.g., Noonan syndrome as a recessive disease) and allowed to profile new RASopathies, novel disease genes and new molecular circuits contributing to the control of RAS-MAPK signaling.

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Section: The Last 5 Years: Novel Rasopathy Genes N...mentioning

confidence: 99%

Section: The Last 5 Years: Novel Rasopathy Genes N...mentioning

confidence: 99%

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Tartaglia

Aoki

Gelb

2022

American J of Med Genetics Pt C

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“…44 Our findings establish RRAS2 germline mutations as a cause of NS. Although previous screening of a cohort of 116 subjects with a clinical diagnosis of NS without a genetic explanation did not identify germline pathogenic RRAS2 variants, 45 the present collaborative effort allowed to identify six unrelated affected individuals. Of the case subjects reported here, two individuals carrying de novo germline NS-causing RRAS2 variants (subjects 1 and 2) were identified among 1,220 samples addressed to Robert Debré Hospital, Paris, for diagnostic testing for NS, between February 2016 and September 2018.…”

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confidence: 92%

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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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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“…We also carried out Sanger sequencing of FLT3 hotspot mutation loci (exons 14, 16, and 20) in a set of 100 independent children with clinically suspected RASopathies who tested negative for Noonan syndrome‐causative genes (leukemia status unknown), to investigate whether germline FLT3 mutations account for a proportion of such patients (primer pairs available upon request).…”

Section: Methodsmentioning

confidence: 99%

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

Smith

Lavoie

Walsh

et al. 2019

Genes Chromosomes & Cancer

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High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD‐ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer‐relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11‐encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10−3), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS‐independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD‐ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

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GermlineRRAS2mutations are not associated with Noonan syndrome

Cited by 7 publications

References 7 publications

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

The molecular genetics of RASopathies: An update on novel disease genes and new disorders

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children

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