<i>SOS1</i> mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Baban, Anwar; Olivini, Nicole; Lepri, Francesca Romana; Calì, Federica; Mucciolo, Mafalda; Digilio, María Cristina; Calcagni, Giulio; Mambro, Corrado Di; Dallapiccola, Bruno; Adorisio, Rachele; Novelli, Antonio; Drago, Fabrizio

doi:10.1002/ajmg.a.61312

Cited by 13 publications

(5 citation statements)

References 28 publications

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“…NS is a genetically heterogeneous disorder caused by mutations in genes that are involved in the RAS/MAPK pathway (Baban et al, 2019; Calcagni et al, 2018). The most frequently mutated gene in NS is PTPN11, accounting for approximately 50% of cases, with individuals carrying PTPN11 mutations often presenting with pulmonary valve stenosis (Tartaglia et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Zheng,

Peng,

Cheng

et al. 2023

Molec Gen & Gen Med

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BackgroundHypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in sarcomeric genes. However, a subset of cases is attributed to genetic disorders unrelated to sarcomeric genes, such as Noonan syndrome (NS) and other RASopathies. In this study, we present a family with a history of sudden cardiac death (SCD) and focus on two adults with syndromic left ventricular hypertrophy (LVH).MethodsClinical evaluations, including echocardiography, were conducted to assess cardiac manifestations. Whole‐exome sequencing was performed to identify potential genetic variants underlying syndromic LVH in the study participants.ResultsWhole‐exome sequencing revealed a missense variant in the RAF1 gene, c.782C>T (p.Pro261Leu). This variant confirmed the diagnosis of NS in the affected individuals.ConclusionThe findings of this study underscore the importance of family history investigation and genetic testing in diagnosing syndromic LVH. By identifying the underlying genetic cause, clinicians can better understand the etiology of RAS‐HCM and its association with SCD in young adults.

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Section: Discussionmentioning

confidence: 99%

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Zheng,

Peng,

Cheng

et al. 2023

Molec Gen & Gen Med

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“…SOS1, a guanine nucleotide exchange factor for Ras protein, plays an important role in the progress of BCR-ABL activation of the Ras/ERK pathway. 30 , 31 However, a relationship between SOS1 and the drug sensitivity or resistance of imatinib was uncovered. In our previous research, SOS1 was a target of miR-181a-5p, a prognostic predictor in cancer, indicating that SOS1 was an oncogene in CML.…”

Section: Discussionmentioning

confidence: 99%

Targeting SOS1 overcomes imatinib resistance with BCR-ABL independence through uptake transporter SLC22A4 in CML

Liu¹,

Li²,

Su³

et al. 2021

Molecular Therapy - Oncolytics

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Resistance to the BCR-ABL inhibitor imatinib mesylate poses a major problem for the treatment of chronic myeloid leukemia. Imatinib resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, sometimes there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent imatinib mesylate resistance remains to be elucidated. SOS1, a guanine nucleotide exchange factor for Ras protein, affects drug sensitivity and resistance to imatinib. The depletion of SOS1 markedly inhibits cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulates the expression of SLC22A4, a member of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that intracellular accumulation of imatinib is accompanied by upregulation of SLC22A4 through SOS1 inhibition in both sensitive and resistant chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in chronic myeloid leukemia cells with resistance and BCR-ABL independence. Altogether these findings indicate that targeting SOS1 inhibition promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport.

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“…The estimated incidence is 1:1000 to 1:2500 live births [2]. Noonan syndrome is caused by genetic mutations related to the RAS-mitogen-activated protein kinase signal transduction pathway [3]. Mutations in the following genes that cause Noonan syndrome have been identified: RAS family GTPase proteins (KRAS, NRAS, RIT1, and RRAS), RAS signal function modulators (PTPN11, SOS1, SOS2, CBL, RASA2, and SHOCS2), and downstream signal transducers (RAF1 and BRAF) [3].…”

Section: Introductionmentioning

confidence: 99%

Electrocardiographic Changes with Age in Japanese Patients with Noonan Syndrome

Ichikawa,

Kuroda,

Ikegawa

et al. 2023

JCDD

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Little information is available on age-related electrocardiographic changes in patients with Noonan syndrome. This single-center study evaluated the electrocardiograms of patients with Noonan syndrome. We divided the patients (n = 112; electrocardiograms, 256) into four groups according to age: G1 (1 month–1 year), G2 (1–6 years), G3 (6–12 years), and G4 (>12 years). Typical Noonan syndrome-related electrocardiographic features such as left-axis deviation, abnormal Q wave, wide QRS complex, and small R wave in precordial leads were detected. A high percentage of QRS axis abnormalities was found in all groups. Significant differences in right-axis deviation (RAD) were noted among the groups: 56.5% of G1 patients showed RAD compared with 33.3% of G2, 21.1% of G3, and 19.2% of G4 patients. The small R was also significantly different among the groups: 32.6% of G1 patients showed a small R wave compared with 14.9% of G2, 8.5% of G3, and 15.4% of G4 patients. Of the 53 patients with Noonan syndrome aged 1 month to 2 years, 18 had T-positive V1 with a higher prevalence of pulmonary stenosis and cardiac interventions. QRS axis abnormalities, small R in V6, and T-positive V1 could help diagnose Noonan syndrome in infants or young children.

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SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Cited by 13 publications

References 28 publications

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Targeting SOS1 overcomes imatinib resistance with BCR-ABL independence through uptake transporter SLC22A4 in CML

Electrocardiographic Changes with Age in Japanese Patients with Noonan Syndrome

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