Clinical analysis of Noonan syndrome caused by RRAS2 mutations and literature review

Yu, Chaonan; Lyn, Nan; Li, Dongxiao; Mei, Shiyue; Liu, Lei; Shang, Qing

doi:10.1016/j.ejmg.2022.104675

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…The RAS molecule has two important domains: the phosphate-binding loop that binds to nucleotide β-phosphate, and Switch I and II, which undergo conformational changes during the hydrolysis reaction from GTP to GDP ( Simanshu et al, 2017 ). Previously reported variants were localized to the phosphate-binding loop and Switch II domains ( Capri et al, 2019 ; Niihori et al, 2019 ; Weinstock and Sadler, 2022 ; Yu et al, 2023 ), and the variants in the present cases were located in the phosphate-binding loop ( Figures 3A,B ). p.Gly24Glu is a novel variant, and in silico predictions revealed a SIFT score of <0.05, which is calculated deleterious, and a polyphen2 score of 1.00, which is calculated probably damaging.…”

Section: Discussionsupporting

confidence: 65%

“…Like other RAS proteins, it is considered to regulate cell proliferation and differentiation via the RAS/MAPK cascade, and somatic mutations in the RRAS2 gene are drivers of tumorigenesis; they have been detected in various tumors such as colon, lung, and skin cancers ( Aoki et al, 2016 ; Clavaín et al, 2023 ). Furthermore, germline RRAS2 mutations have been reported to cause NS ( Capri et al, 2019 ; Niihori et al, 2019 ; Weinstock and Sadler, 2022 ; Yu et al, 2023 ). However, there are relatively few reports, and it is unclear what type of RRAS2 variants cause the disease.…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of RRAS2 pathogenic variants with a Noonan-like phenotype

Iida,

Igarashi,

Fukunaga

et al. 2024

Front. Genet.

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Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like low-molecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis.Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed.Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway.Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-of-function RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Functional analysis of RRAS2 pathogenic variants with a Noonan-like phenotype

Iida,

Igarashi,

Fukunaga

et al. 2024

Front. Genet.

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“…Noonan syndrome (NS [MIM: 163950]) is an autosomal dominant or recessive disorder, characterized by short stature, variable developmental delay, distinctive facial features, and congenital cardiac defects, as well as variable neurocognitive impairment and predisposition to malignancies (Roberts et al., 2013; Tartaglia et al., 2011; Yu et al., 2023). Approximately 80% of NS‐positive individuals have mutations in genes whose products are involved in the RAS/mitogen‐activating protein kinase (MAPK) pathway.…”

Section: Introductionmentioning

confidence: 99%

The RRAS2 pathogenic variant (c.67G>T; p. Gly23Cys) produces Noonan syndrome with embryonal rhabdomyosarcoma

Zeng,

Wang,

Zhu

et al. 2023

Molec Gen & Gen Med

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BackgroundNoonan syndrome (NS) due to the RRAS2 gene, the pathogenic variant is an extremely rare RASopathies. Our objective was to identify the potential site of RRAS2, combined with the literature review, to find the correlation between clinical phenotype and genotype. De novo missense mutations affect different aspects of the RRAS2 function, leading to hyperactivation of the RAS‐MAPK signaling cascade.MethodsConventional G‐banding was used to analyze the chromosome karyotype of the patient. Copy number variation sequencing (CNV‐seq) was used to detect the chromosomal gene microstructure of the patient and her parents. The exomes of the patient and her parents were sequenced using trio‐based whole exome sequencing (trio‐WES) technology. The candidate variant was verified by Sanger sequencing. The pathogenicity of the variant was predicted with a variety of bioinformatics tools.ResultsChromosome analysis of the proband revealed 46, XX, and no abnormality was found by CNV‐seq. After sequencing and bioinformatics filtering, the variant of RRAS2(c.67G>T; p. Gly23Cys) was found in the proband, while the mutation was absent in her parents. To the best of our knowledge, our patient was with the typical Noonan syndrome, such as short stature, facial dysmorphism, and developmental delay. Furthermore, our study is the first case of NS with embryonal rhabdomyosarcoma (ERMS) caused by the RRAS2 gene mutation reported in China.ConclusionsOur investigations suggested that the heterozygous missense of RRAS2 may be a potential causal variant in a rare cause of Noonan syndrome, expanding our understanding of the causally relevant mutations for this disorder.

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