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.
Highlights
Germline mutations that activate RAS/MAPK signaling are responsible for the “RASopathies,” a group of rare human developmental diseases that affect more than 400,000 individuals in the United States alone
We performed a comprehensive analysis of the molecular determinants of Costello syndrome (CS) using untargeted proteomics, bioenergetics, and molecular biology methods on a collection of biological models: tissues of a HRAS p.G12S CS mouse model, skin fibroblasts from patients with CS, CS hiPSC-CMs, human skin fibroblasts transduced with mutant forms of HRAS p.G12S and HRAS p.G12A, and a HRAS p.G12V zebrafish model of CS
The original CS mouse model used in our study was generated by a knockin of a mutant HRAS p.G12S gene in C57BL/6 animals and developed hypertrophic cardiomyopathy (HCM)
Summary
Germline mutations that activate RAS/MAPK signaling are responsible for the “RASopathies,” a group of rare human developmental diseases that affect more than 400,000 individuals in the United States alone. Costello syndrome (CS) has been described as a multiple congenital anomaly syndrome caused by heterozygous activating germline mutations in HRAS [1]. Most individuals affected by CS carry a mutation in HRAS at the G12 position, and more than 80% of individuals with CS have a p.G12S substitution. Most children with CS exhibit an increased birth weight, dysmorphic craniofacial features, failure to thrive, and gastroesophageal reflux with oral aversion, especially during the newborn period. CS can involve the skin, with excessive wrinkling and redun-
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