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HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models.

dc.rights.licenseopenen_US
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorDARD, Laetitia
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorHUBERT, Christophe
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorESTEVES, Pauline
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorBLANCHARD, Wendy
dc.contributor.authorBOU ABOUT, Ghina
dc.contributor.authorBALDASSERONI, Lyla
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorDUMON, Elodie
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorANGELINI, Chloe
dc.contributor.authorDELOURME, Megane
dc.contributor.authorGUYONNET-DUPERAT, Veronique
dc.contributor.authorCLAVEROL, Stephane
hal.structure.identifierAZELEAD
dc.contributor.authorFONTENILLE, Laura
dc.contributor.authorKISSA, Karima
dc.contributor.authorSEGUELA, Pierre-Emmanuel
hal.structure.identifierCentre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] [CRCTB]
dc.contributor.authorTHAMBO, Jean-Benoit
dc.contributor.authorNICOLAS, Levy
dc.contributor.authorHERAULT, Yann
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorBELLANCE, Nadege
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorDIAS AMOEDO, Nivea
dc.contributor.authorMAGDINIER, Frederique
dc.contributor.authorSORG, Tania
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorLACOMBE, Didier
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorROSSIGNOL, Rodrigue
dc.date.accessioned2023-07-05T14:48:43Z
dc.date.available2023-07-05T14:48:43Z
dc.date.issued2022-04-15
dc.identifier.issn1558-8238en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/183313
dc.description.abstractEnGermline mutations that activate genes in the canonical RAS/MAPK signaling pathway are responsible for rare human developmental disorders known as RASopathies. Here, we analyzed the molecular determinants of Costello syndrome (CS) using a mouse model expressing HRAS p.G12S, patient skin fibroblasts, hiPSC-derived human cardiomyocytes, a HRAS p.G12V zebrafish model, and human fibroblasts expressing lentiviral constructs carrying HRAS p.G12S or HRAS p.G12A mutations. The findings revealed alteration of mitochondrial proteostasis and defective oxidative phosphorylation in the heart and skeletal muscle of CS mice that were also found in the cell models of the disease. The underpinning mechanisms involved the inhibition of the AMPK signaling pathway by mutant forms of HRAS, leading to alteration of mitochondrial proteostasis and bioenergetics. Pharmacological activation of mitochondrial bioenergetics and quality control restored organelle function in HRAS p.G12A and p.G12S cell models, reduced left ventricle hypertrophy in CS mice, and diminished the occurrence of developmental defects in the CS zebrafish model. Collectively, these findings highlight the importance of mitochondrial proteostasis and bioenergetics in the pathophysiology of RASopathies and suggest that patients with CS may benefit from treatment with mitochondrial modulators.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enAMP-Activated Protein Kinases
dc.subject.enAnimals
dc.subject.enCostello Syndrome
dc.subject.enGerm-Line Mutation
dc.subject.enHomeostasis
dc.subject.enHumans
dc.subject.enMice
dc.subject.enProto-Oncogene Proteins p21(ras)
dc.subject.enZebrafish
dc.title.enHRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models.
dc.title.alternativeJ Clin Investen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1172/JCI131053en_US
dc.subject.halSciences du Vivant [q-bio]/Génétiqueen_US
dc.identifier.pubmed35230976en_US
bordeaux.journalThe Journal of clinical investigationen_US
bordeaux.volume132en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue8en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exportfalse
workflow.import.sourcepubmed
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