PUBLICATION
RAF1 mutations in childhood-onset dilated cardiomyopathy
- Authors
- Dhandapany, P.S., Razzaque, M.A., Muthusami, U., Kunnoth, S., Edwards, J.J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D.S., Rani, B., Govindaraj, P., Flex, E., Yokota, T., Furutani, M., Nishizawa, T., Nakanishi, T., Robbins, J., Limongelli, G., Hajjar, R.J., Lebeche, D., Bahl, A., Khullar, M., Rathinavel, A., Sadler, K.C., Tartaglia, M., Matsuoka, R., Thangaraj, K., Gelb, B.D.
- ID
- ZDB-PUB-140513-67
- Date
- 2014
- Source
- Nature Genetics 46(6): 635-9 (Journal)
- Registered Authors
- Sadler Edepli, Kirsten C.
- Keywords
- none
- MeSH Terms
-
- Adult
- Age of Onset
- Aged
- Amino Acid Sequence
- Animals
- Cardiomyopathy, Dilated/ethnology
- Cardiomyopathy, Dilated/genetics*
- 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
- Mutation*
- Phenotype
- Prevalence
- Proto-Oncogene Proteins c-raf/genetics*
- Sequence Homology, Amino Acid
- Sirolimus/chemistry
- Zebrafish
- PubMed
- 24777450 Full text @ Nat. Genet.
Citation
Dhandapany, P.S., Razzaque, M.A., Muthusami, U., Kunnoth, S., Edwards, J.J., Mulero-Navarro, S., Riess, I., Pardo, S., Sheng, J., Rani, D.S., Rani, B., Govindaraj, P., Flex, E., Yokota, T., Furutani, M., Nishizawa, T., Nakanishi, T., Robbins, J., Limongelli, G., Hajjar, R.J., Lebeche, D., Bahl, A., Khullar, M., Rathinavel, A., Sadler, K.C., Tartaglia, M., Matsuoka, R., Thangaraj, K., Gelb, B.D. (2014) RAF1 mutations in childhood-onset dilated cardiomyopathy. Nature Genetics. 46(6):635-9.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping