Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species

Carpentieri, Giovanna; Leoni, Chiara; Pietraforte, Donatella; Cecchetti, Serena; Iorio, Egidio; Belardo, Antonio; Pietrucci, Daniele; Nottia, Michela Di; Pajalunga, Deborah; Megiorni, Francesca; Mercurio, Laura; Tatti, Massimo; Camero, Simona; Marchese, Cinzia; Rizza, Teresa; Tirelli, Valentina; Onesimo, Roberta; Carrozzo, Rosalba; Rinalducci, Sara; Chillemi, Giovanni; Zampino, Giuseppe; Tartaglia, Marco; Flex, Elisabetta

doi:10.1093/hmg/ddab270

Cited by 6 publications

(4 citation statements)

References 74 publications

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“…The recent documentation of increased basal metabolism and resting energy expenditure surely needs to be supported by future studies on larger cohorts to confirm its negative impact on growth and metabolic profile. 56 , 60 …”

Section: Discussionmentioning

confidence: 99%

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Multidisciplinary Management of Costello Syndrome: Current Perspectives

Leoni¹,

Viscogliosi²,

Tartaglia³

et al. 2022

JMDH

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Costello syndrome (CS) is a rare neurodevelopmental disorder caused by germline mutations in HRAS . It belongs among the RASopathies, a group of syndromes characterized by alterations in components of the RAS/MAPK signaling pathway and sharing overlapping phenotypes. Its typical features include a distinctive facial appearance, growth delay, intellectual disability, ectodermal, cardiac, and musculoskeletal abnormalities, and cancer predisposition. Due to the several comorbidities having a strong impact on the quality of life, a multidisciplinary team is essential in the management of such a condition from infancy to adult age, to promptly address any detected issue and to develop appropriate personalized follow-up protocols and treatment strategies. With the present paper we aim to highlight the core and ancillary medical disciplines involved in managing the health challenges characterizing CS from pediatric to adult age, according to literature and to our large clinical experience.

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Section: Discussionmentioning

confidence: 99%

“…Some factors may be at the base of the increased energy expenditure in CS such as heart defects, lung issues, infections, and endocrine dysfunction, but the intrinsic effect of HRAS mutation has otherwise been primarily considered. 56 , 60 …”

Section: Core and Ancillary Medical Specialties In Pediatric Age: Com...mentioning

confidence: 99%

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Leoni¹,

Viscogliosi²,

Tartaglia³

et al. 2022

JMDH

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“…These patients present with marked failure to thrive substantially due to muscle tissue wasting rather a decrease in adipose tissue ( 44 ). A possible correlation between metabolism and control of energy storage has been hypothesized ( 45 , 46 ), which may involve two important hormones involved in unsatiety signals (insulin and leptin) and the RAS/MAPK pathway. As proof, patients with CS display an increased resting energy expenditure and a high calorie intake compared with the recommended levels of energy intake ( 47 ).…”

Section: Growth and Growth Hormone-igf-1 Axis In Noonan Syndromementioning

confidence: 99%

Inside the Noonan “universe”: Literature review on growth, GH/IGF axis and rhGH treatment: Facts and concerns

Stagi

Ferrari

et al. 2022

Front. Endocrinol.

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Noonan syndrome (NS) is a disorder characterized by a typical facial gestalt, congenital heart defects, variable cognitive deficits, skeletal defects, and short stature. NS is caused by germline pathogenic variants in genes coding proteins with a role in the RAS/mitogen-activated protein kinase signaling pathway, and it is typically associated with substantial genetic and clinical complexity and variability. Short stature is a cardinal feature in NS, with evidence indicating that growth hormone (GH) deficiency, partial GH insensitivity, and altered response to insulin-like growth factor I (IGF-1) are contributing events for growth failure in these patients. Decreased IGF-I, together with low/normal responses to GH pharmacological provocation tests, indicating a variable presence of GH deficiency/resistance, in particular in subjects with pathogenic PTPN11 variants, are frequently reported. Nonetheless, short- and long-term studies have demonstrated a consistent and significant increase in height velocity (HV) in NS children and adolescents treated with recombinant human GH (rhGH). While the overall experience with rhGH treatment in NS patients with short stature is reassuring, it is difficult to systematically compare published data due to heterogeneous protocols, potential enrolment bias, the small size of cohorts in many studies, different cohort selection criteria and varying durations of therapy. Furthermore, in most studies, the genetic information is lacking. NS is associated with a higher risk of benign and malignant proliferative disorders and hypertrophic cardiomyopathy, and rhGH treatment may further increase risk in these patients, especially as dosages vary widely. Herein we provide an updated review of aspects related to growth, altered function of the GH/IGF axis and cell response to GH/IGF stimulation, rhGH treatment and its possible adverse events. Given the clinical variability and genetic heterogeneity of NS, treatment with rhGH should be personalized and a conservative approach with judicious surveillance is recommended. Depending on the genotype, an individualized follow-up and close monitoring during rhGH treatments, also focusing on screening for neoplasms, should be considered.

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“…Dysregulation of the RAS-MAPK pathway contributes to the control of metabolism and energy storage (1). Energy metabolism is consistently found to be dysregulated in RASopathies (2)(3)(4)(5)(6), which constitute a family of disorders caused by mutations in genes encoding key transducers participating in the RAS-MAPK signalling cascade (7,8). Metabolic and nutritional aspects in RASopathies are, however, still poorly explored (9).…”

Section: Introductionmentioning

confidence: 99%

Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype

Tamburrino,

Mazzanti,

Scarano

et al. 2023

Front. Endocrinol.

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BackgroundRASopathies are developmental disorders caused by dysregulation of the RAS-MAPK signalling pathway, which contributes to the modulation of multiple extracellular signals, including hormones and growth factors regulating energetic metabolism, including lipid synthesis, storage, and degradation.Subjects and methodsWe evaluated the body composition and lipid profiles of a single-centre cohort of 93 patients with a molecularly confirmed diagnosis of RASopathy by assessing height, BMI, and total cholesterol, HDL, triglycerides, apolipoprotein, fasting glucose, and insulin levels, in the context of a cross sectional and longitudinal study. We specifically investigated and compared anthropometric and haematochemistry data between the Noonan syndrome (NS) and Mazzanti syndrome (NS/LAH) groups.ResultsAt the first evaluation (9.5 ± 6.2 years), reduced growth (-1.80 ± 1.07 DS) was associated with a slightly reduced BMI (-0.34 DS ± 1.15 DS). Lipid profiling documented low total cholesterol levels (< 5th percentile) in 42.2% of the NS group; in particular, in 48.9% of PTPN11 patients and in 28.6% of NS/LAH patients compared to the general population, with a significant difference between males and females. A high proportion of patients had HDL levels lower than the 26th percentile, when compared to the age- and sex-matched general population. Triglycerides showed an increasing trend with age only in NS females. Genotype-phenotype correlations were also evident, with particularly reduced total cholesterol in about 50% of patients with PTPN11 mutations with LDL-C and HDL-C tending to decrease during puberty. Similarly, apolipoprotein A1 and apolipoprotein B deficits were documented, with differences in prevalence associated with the genotype for apolipoprotein A1. Fasting glucose levels and HOMA-IR were within the normal range.ConclusionThe present findings document an unfavourable lipid profile in subjects with NS, in particular PTPN11 mutated patients, and NS/LAH. Further studies are required to delineate the dysregulation of lipid metabolism in RASopathies more systematically and confirm the occurrence of previously unappreciated genotype-phenotype correlations involving the metabolic profile of these disorders.

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Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species

Cited by 6 publications

References 74 publications

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Multidisciplinary Management of Costello Syndrome: Current Perspectives

Inside the Noonan “universe”: Literature review on growth, GH/IGF axis and rhGH treatment: Facts and concerns

Lipid profile in Noonan syndrome and related disorders: trend by age, sex and genotype

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