RAF1 mutations in childhood-onset dilated cardiomyopathy

Perundurai S. Dhandapany, Md Abdur Razzaque, Uthiralingam Muthusami, Sreejith Kunnoth, Jonathan J. Edwards, Sonia Mulero-Navarro, Ilan Riess, Sherly Pardo, Jipo Sheng, Deepa Selvi Rani, Bindu Rani, Periyasamy Govindaraj, Elisabetta Flex, Tomohiro Yokota, Michiko Furutani, Tsutomu Nishizawa, Toshio Nakanishi, Jeffrey Robbins, Giuseppe Limongelli, Roger J. HajjarDjamel Lebeche, Ajay Bahl, Madhu Khullar, Andiappan Rathinavel, Kirsten Sadler Edepli, Marco Tartaglia, Rumiko Matsuoka, Kumarasamy Thangaraj, Bruce D. Gelb

Research output: Contribution to journalArticle

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 1/49% 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.

Original languageEnglish (US)
Pages (from-to)635-639
Number of pages5
JournalNature Genetics
Volume46
Issue number6
DOIs
StatePublished - Jan 1 2014

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Dilated Cardiomyopathy
Mutation
Zebrafish
Sirolimus
Genetic Therapy
Phosphotransferases
Embryonic Structures
Heart Failure
Phenotype
Therapeutics
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Dhandapany, P. S., Razzaque, M. A., Muthusami, U., Kunnoth, S., Edwards, J. J., Mulero-Navarro, S., ... Gelb, B. D. (2014). RAF1 mutations in childhood-onset dilated cardiomyopathy. Nature Genetics, 46(6), 635-639. https://doi.org/10.1038/ng.2963

RAF1 mutations in childhood-onset dilated cardiomyopathy. / Dhandapany, Perundurai S.; Razzaque, Md Abdur; Muthusami, Uthiralingam; Kunnoth, Sreejith; Edwards, Jonathan J.; Mulero-Navarro, Sonia; Riess, Ilan; Pardo, Sherly; Sheng, Jipo; Rani, Deepa Selvi; Rani, Bindu; Govindaraj, Periyasamy; Flex, Elisabetta; Yokota, Tomohiro; Furutani, Michiko; Nishizawa, Tsutomu; Nakanishi, Toshio; Robbins, Jeffrey; Limongelli, Giuseppe; Hajjar, Roger J.; Lebeche, Djamel; Bahl, Ajay; Khullar, Madhu; Rathinavel, Andiappan; Sadler Edepli, Kirsten; Tartaglia, Marco; Matsuoka, Rumiko; Thangaraj, Kumarasamy; Gelb, Bruce D.

In: Nature Genetics, Vol. 46, No. 6, 01.01.2014, p. 635-639.

Research output: Contribution to journalArticle

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 Edepli, K, Tartaglia, M, Matsuoka, R, Thangaraj, K & Gelb, BD 2014, 'RAF1 mutations in childhood-onset dilated cardiomyopathy', Nature Genetics, vol. 46, no. 6, pp. 635-639. https://doi.org/10.1038/ng.2963
Dhandapany PS, Razzaque MA, Muthusami U, Kunnoth S, Edwards JJ, Mulero-Navarro S et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nature Genetics. 2014 Jan 1;46(6):635-639. https://doi.org/10.1038/ng.2963
Dhandapany, Perundurai S. ; Razzaque, Md Abdur ; Muthusami, Uthiralingam ; Kunnoth, Sreejith ; Edwards, Jonathan J. ; Mulero-Navarro, Sonia ; Riess, Ilan ; Pardo, Sherly ; Sheng, Jipo ; Rani, Deepa Selvi ; Rani, Bindu ; Govindaraj, Periyasamy ; Flex, Elisabetta ; Yokota, Tomohiro ; Furutani, Michiko ; Nishizawa, Tsutomu ; Nakanishi, Toshio ; Robbins, Jeffrey ; Limongelli, Giuseppe ; Hajjar, Roger J. ; Lebeche, Djamel ; Bahl, Ajay ; Khullar, Madhu ; Rathinavel, Andiappan ; Sadler Edepli, Kirsten ; Tartaglia, Marco ; Matsuoka, Rumiko ; Thangaraj, Kumarasamy ; Gelb, Bruce D. / RAF1 mutations in childhood-onset dilated cardiomyopathy. In: Nature Genetics. 2014 ; Vol. 46, No. 6. pp. 635-639.
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