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, Kirsten C. ; Tartaglia, Marco ; Matsuoka, Rumiko ; Thangaraj, Kumarasamy ; Gelb, Bruce D. (2014) RAF1 mutations in childhood-onset dilated cardiomyopathy Nature Genetics, 46 (6). pp. 635-639. ISSN 1061-4036

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Official URL: http://www.nature.com/ng/journal/v46/n6/full/ng.29...

Related URL: http://dx.doi.org/10.1038/ng.2963


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.

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