HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models
- PMID: 35230976
- PMCID: PMC9012293
- DOI: 10.1172/JCI131053
HRAS germline mutations impair LKB1/AMPK signaling and mitochondrial homeostasis in Costello syndrome models
Abstract
Germline 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.
Keywords: Bioenergetics; Metabolism.
Conflict of interest statement
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g125.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g126.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g127.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g128.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g129.gif)
![Figure 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g130.gif)
![Figure 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g131.gif)
![Figure 8](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9012293/bin/jci-132-131053-g132.gif)
Comment in
-
Mitochondria and the future of RASopathies: the emergence of bioenergetics.J Clin Invest. 2022 Apr 15;132(8):1-5. doi: 10.1172/JCI157560. J Clin Invest. 2022. PMID: 35426371 Free PMC article.
Similar articles
-
Mitochondria and the future of RASopathies: the emergence of bioenergetics.J Clin Invest. 2022 Apr 15;132(8):1-5. doi: 10.1172/JCI157560. J Clin Invest. 2022. PMID: 35426371 Free PMC article.
-
HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.J Hum Genet. 2011 Oct;56(10):707-15. doi: 10.1038/jhg.2011.85. Epub 2011 Aug 18. J Hum Genet. 2011. PMID: 21850009
-
An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.Am J Med Genet A. 2015 Sep;167A(9):2085-97. doi: 10.1002/ajmg.a.37128. Epub 2015 Apr 25. Am J Med Genet A. 2015. PMID: 25914166 Free PMC article.
-
Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations.Genet Med. 2012 Mar;14(3):285-92. doi: 10.1038/gim.0b013e31822dd91f. Genet Med. 2012. PMID: 22261753 Review.
-
Costello syndrome with special cutaneous manifestations and HRAS G12D mutation: A case report and literature review.Mol Genet Genomic Med. 2021 Jun;9(6):e1690. doi: 10.1002/mgg3.1690. Epub 2021 May 1. Mol Genet Genomic Med. 2021. PMID: 33932139 Free PMC article. Review.
Cited by
-
Non-Mammalian Models for Understanding Neurological Defects in RASopathies.Biomedicines. 2024 Apr 10;12(4):841. doi: 10.3390/biomedicines12040841. Biomedicines. 2024. PMID: 38672195 Free PMC article. Review.
-
In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.Int J Mol Sci. 2024 Feb 1;25(3):1734. doi: 10.3390/ijms25031734. Int J Mol Sci. 2024. PMID: 38339013 Free PMC article. Review.
-
Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.JCI Insight. 2024 Feb 22;9(4):e174097. doi: 10.1172/jci.insight.174097. JCI Insight. 2024. PMID: 38271099 Free PMC article.
-
The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.Am J Med Genet A. 2024 Apr;194(4):e63477. doi: 10.1002/ajmg.a.63477. Epub 2023 Nov 15. Am J Med Genet A. 2024. PMID: 37969032
-
Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Front Endocrinol (Lausanne). 2023 Oct 27;14:1231828. doi: 10.3389/fendo.2023.1231828. eCollection 2023. Front Endocrinol (Lausanne). 2023. PMID: 37964950 Free PMC article. Review.
References
-
- Costello J. A new syndrome. N Z Med J. 1971;74:397
-
- Siwik ES, et al. Cardiac disease in Costello syndrome. Pediatrics. 1998;101(4 pt 1):706–709. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous