De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. Hum Genet 2016 Aug;135(8):909-917
Date
05/29/2016Pubmed ID
27234373Pubmed Central ID
PMC4947566DOI
10.1007/s00439-016-1685-3Scopus ID
2-s2.0-84971006595 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
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.
Author List
Long PA, Zimmermann MT, Kim M, Evans JM, Xu X, Olson TMAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsCardiomyopathy, Dilated
Exome
Female
Gene Expression Regulation
Genetic Association Studies
Genetic Heterogeneity
Genetic Linkage
Genotype
Humans
Infant
Infant, Newborn
Male
Mechanistic Target of Rapamycin Complex 1
Monomeric GTP-Binding Proteins
Multiprotein Complexes
Mutation, Missense
Pedigree
TOR Serine-Threonine Kinases
