1. RAF1 mutations in childhood-onset dilated cardiomyopathy.
- Author
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Dhandapany PS, Razzaque MA, Muthusami U, Kunnoth S, Edwards JJ, Mulero-Navarro S, Riess I, Pardo S, Sheng J, Rani DS, Rani B, Govindaraj P, Flex E, Yokota T, Furutani M, Nishizawa T, Nakanishi T, Robbins J, Limongelli G, Hajjar RJ, Lebeche D, Bahl A, Khullar M, Rathinavel A, Sadler KC, Tartaglia M, Matsuoka R, Thangaraj K, and Gelb BD
- Subjects
- Adult, Age of Onset, Aged, Amino Acid Sequence, Animals, Cardiomyopathy, Dilated ethnology, Case-Control Studies, Cohort Studies, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Fibroblasts metabolism, HEK293 Cells, Humans, India, Japan, Male, Mice, Middle Aged, Molecular Sequence Data, Phenotype, Prevalence, Sequence Homology, Amino Acid, Sirolimus chemistry, Zebrafish, Cardiomyopathy, Dilated genetics, Mutation, Proto-Oncogene Proteins c-raf genetics
- Abstract
Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.
- Published
- 2014
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