title: De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy.
abstract: Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder with variable age-dependent penetrance. We sought to identify the genetic underpinnings of syndromic, sporadic DCM in a newborn female diagnosed in utero. Postnatal evaluation revealed ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms. Comprehensive metabolic and genetic testing, including chromosomal microarray, mitochondrial DNA and targeted RASopathy gene sequencing, and clinical whole exome sequencing for known cardiomyopathy genes was non-diagnostic. Following exclusion of asymptomatic DCM in the parents, trio-based whole exome sequencing was carried out on a research basis, filtering for rare, predicted deleterious de novo and recessive variants. An unreported de novo S75Y mutation was discovered in RRAGC, encoding Ras-related GTP binding C, an essential GTPase in nutrient-activated mechanistic target of rapamycin complex 1 (mTORC1) signaling. In silico protein modeling and molecular dynamics simulation predicted the mutation to disrupt ligand interactions and increase the GDP-bound state. Overexpression of RagC(S75Y) rendered AD293 cells partially insensitive to amino acid deprivation, resulting in increased mTORC1 signaling compared to wild-type RagC. These findings implicate mTORC1 dysregulation through a gain-of-function mutation in RagC as a novel molecular basis for syndromic forms of pediatric heart failure, and expand genotype-phenotype correlation in RASopathy-related syndromes.
authors.affiliation: Mayo Graduate School, Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic, Rochester, MN.|Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester MN.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Long
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Zimmermann
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Maengjo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester MN.|Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine; Mayo Clinic, Rochester, MN.|Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Olson
mesh_terms: D000367:Age Factors; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; C430722:RRAGC protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins