De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy

详细信息    查看全文

• 作者：Pamela A. Long ; Michael T. Zimmermann ; Maengjo Kim ; Jared M. Evans…
• 刊名：Human Genetics
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：135
• 期：8
• 页码：909-917
• 全文大小：2,855 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Human Genetics
  Molecular Medicine
  Internal Medicine
  Metabolic Diseases
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1203
• 卷排序：135

文摘

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 RagCS75Y 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.M. T. Zimmermann and M. Kim contributed equally to this work.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1685-3) contains supplementary material, which is available to authorized users.