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. Hajjar & 9 others Djamel 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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    AU - Kunnoth, Sreejith

    AU - Edwards, Jonathan J.

    AU - Mulero-Navarro, Sonia

    AU - Riess, Ilan

    AU - Pardo, Sherly

    AU - Sheng, Jipo

    AU - Rani, Deepa Selvi

    AU - Rani, Bindu

    AU - Govindaraj, Periyasamy

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    AU - Yokota, Tomohiro

    AU - Furutani, Michiko

    AU - Nishizawa, Tsutomu

    AU - Nakanishi, Toshio

    AU - Robbins, Jeffrey

    AU - Limongelli, Giuseppe

    AU - Hajjar, Roger J.

    AU - Lebeche, Djamel

    AU - Bahl, Ajay

    AU - Khullar, Madhu

    AU - Rathinavel, Andiappan

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    AU - Tartaglia, Marco

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