Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations

Yaoita, Masako; Niihori, Tetsuya; Mizuno, Seiji; Okamoto, Nobuhiko; Hayashi, Shinya; Watanabe, Atsushi; Yokozawa, Masato; Suzumura, Hiroshi; Nakahara, A; Nakano, Yusuke; Hokosaki, Tatsunori; Ohmori, Ayumi; Sawada, Hirofumi; Migita, Ohsuke; Mima, Aya; Lapunzina, Pablo; Santos‐Simarro, Fernando; García‐Miñaúr, Sixto; Ogata, Tsutomu; Kawame, Hiroshi; Kurosawa, Kenji; Ohashi, Hirofumi; Inoue, Shin–Ichi; Matsubara, Yoichi; Kure, Shigeo; Aoki, Yoko

doi:10.1007/s00439-015-1627-5

Cited by 82 publications

(99 citation statements)

References 47 publications

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“…The encoded protein is involved in a wide variety of cellular processes, including cell proliferation, differen-tiation, and survival. It has been shown that different pathogenic variants in the RIT1 gene cause autosomal dominant Noonan syndrome through a gain-of-function mechanism resulting in increased RAS/MAPK signaling [Bertola et al, 2014;Gos et al, 2014;Milosavljević et al, 2016;Yaoita et al, 2016]. Recent reports have demonstrated that copy number variations containing disease-causing genes of RAS/MAPK pathway may be a pathogenetic mechanism for the etiology of RASopathies or related disorders [Graham et al, 2009;Luo et al, 2012;Chen et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

Aleksiūnienė

Preikšaitienė²,

Morkūnienė³

et al. 2018

Cytogenet Genome Res

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Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features.

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Section: Discussionmentioning

confidence: 99%

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

Aleksiūnienė

Preikšaitienė²,

Morkūnienė³

et al. 2018

Cytogenet Genome Res

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“…Initially, nine different missense mutations in RIT1 were reported in 17 of 180 individuals with NS with no mutations in the previously known NS genes [Aoki et al, 2013]. Others [Bertola et al, 2014;Chen et al, 2014;Gos et al, 2014;Justino et al, 2015;Koenighofer et al, 2016;Yaoita et al, 2016)] described additional patients with mutations in RIT1. In line with the observations in other NS associated genes, functional studies showed that mutant RIT1 results in an enhanced signaling activity of the RAS-MAPK pathway [Aoki et al, 2013;Chen et al, 2014;Koenighofer et al, 2016;Yaoita et al, 2016].…”

Section: Introductionmentioning

confidence: 98%

“…Others [Bertola et al, 2014;Chen et al, 2014;Gos et al, 2014;Justino et al, 2015;Koenighofer et al, 2016;Yaoita et al, 2016)] described additional patients with mutations in RIT1. In line with the observations in other NS associated genes, functional studies showed that mutant RIT1 results in an enhanced signaling activity of the RAS-MAPK pathway [Aoki et al, 2013;Chen et al, 2014;Koenighofer et al, 2016;Yaoita et al, 2016]. The aim of our study was to further delineate the clinical phenotype by presenting two patients with novel phenotypic manifestations of a RIT1 mutation and by providing an overview of the current literature on RIT1.…”

Section: Introductionmentioning

confidence: 99%

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

Milosavljević

Overwater

Tamminga

et al. 2016

American J of Med Genetics Pt A

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Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

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“…6, E and F). The A57G and Y89H mutations were highly activated in the RBD pulldown, and have been shown to enhance activation of ERK (5,8) and ELK (4,9).…”

Section: Structural Considerations Of Rit1 Disease-associatedmentioning

confidence: 99%

“…ERK (5), and activation of ELK (4,9). In addition to fast nucleotide exchange, the S35T mutant also exhibited reduced GTPase activity, which is likely related to perturbation of the Mg 2ϩ ion.…”

Section: Structural Considerations Of Rit1 Disease-associatedmentioning

confidence: 99%

Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1)

Fang

Marshall

Yin³

et al. 2016

Journal of Biological Chemistry

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RAS-like protein expressed in many tissues 1 (RIT1) is a disease-associated RAS subfamily small guanosine triphosphatase (GTPase). Recent studies revealed that germ-line and somatic RIT1 mutations can cause Noonan syndrome (NS), and drive proliferation of lung adenocarcinomas, respectively, akin to RAS mutations in these diseases. However, the locations of these RIT1 mutations differ significantly from those found in RAS, and do not affect the three mutational "hot spots" of RAS. Moreover, few studies have characterized the GTPase cycle of RIT1 and its disease-associated mutants. Here we developed a realtime NMR-based GTPase assay for RIT1 and investigated the effect of disease-associated mutations on GTPase cycle. RIT1 exhibits an intrinsic GTP hydrolysis rate similar to that of H-RAS, but its intrinsic nucleotide exchange rate is ϳ4-fold faster, likely as a result of divergent residues near the nucleotide binding site. All of the disease-associated mutations investigated increased the GTP-loaded, activated state of RIT1 in vitro, but they could be classified into two groups with different intrinsic GTPase properties. The S35T, A57G, and Y89H mutants exhibited more rapid nucleotide exchange, whereas F82V and T83P impaired GTP hydrolysis. A RAS-binding domain pulldown assay indicated that RIT1 A57G and Y89H were highly activated in HEK293T cells, whereas T83P and F82V exhibited more modest activation. All five mutations are associated with NS, whereas two (A57G and F82V) have also been identified in urinary tract cancers and myeloid malignancies. Characterization of the effects on the GTPase cycle of RIT1 disease-associated mutations should enable better understanding of their role in disease processes.Small GTPase proteins regulate signal transduction through a conserved "switch" mechanism (1). The GTP-bound state of these proteins adopts an activated conformation that can bind to and activate downstream effector proteins, thus driving signal transduction. Hydrolysis of GTP to GDP then terminates the signaling event (Fig. 1A). GTPase proteins have the ability to hydrolyze GTP (intrinsic hydrolysis), and to become reactivated by releasing GDP and binding a new molecule of GTP (intrinsic exchange), although both of these processes occur slowly. Most GTPases can be rapidly inactivated by GTPaseactivating proteins (GAPs), 6 which catalyze nucleotide hydrolysis, whereas guanine nucleotide exchange factors (GEFs) promote their reactivation by accelerating the exchange of GDP for GTP. Mutations in small GTPases or their GAPs and GEFs can disrupt this GTPase cycle and result in diseases such as cancer and developmental disorders (2, 3).Recent genetic analyses of Noonan syndrome (NS) patients have shown that mutations in RIT1 can cause this condition (Fig. 1B and Table 1) (4 -11). NS is a "RASopathy" characterized by short stature, distinctive facial features, and heart defects, caused by mutations in several RAS signaling pathway genes, including PTPN11, SOS1/2, RAF1, KRAS, NRAS,. RIT1 belongs to the RAS subfamily, sha...

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Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations

Cited by 82 publications

References 47 publications

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1)

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