RAF1 mutations in childhood-onset dilated cardiomyopathy
Authors: Uthiralingam Muthusami
Ilan Riess
Sreejith Kunnoth
Perundurai S Dhandapany
Tsutomu Nishizawa
Giuseppe Limongelli
Kirsten C Sadler
Tomohiro Yokota
Madhu Khullar
Bindhu Rani
Djamel Lebeche
Andiappan Rathinavel
Periyasamy Govindaraj
Roger J Hajjar
Bruce D Gelb
Sonia Mulero-Navarro
Sherly Pardo
Md Abdur Razzaque
Jonathan J Edwards
Rumiko Matsuoka
Michiko Furutani
Marco Tartaglia
Kumarasamy Thangaraj
Jeffrey Robbins
Toshio Nakanishi
Deepa Selvi Rani
Elisabetta Flex
Ajay Bahl
Jipo Sheng
Journal: Nature Genetics (2014)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Dilated cardiomyopathy; sarcomeric gene mutations; RAF1 mutations; biochemical studies; kinase activity
Affiliations: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA., The Mindich Child Health and Development Institute, Hess Center for Science and Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA., The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India., Recinto de Ciencias M√©dicas, Universidad de Puerto Rico, San Juan, Puerto Rico., Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA., Center for Cellular and Molecular Biology, Hyderabad, India., Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India., Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, India., Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanit√†, Rome, Italy., International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan., Department of Pediatric Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan., Monaldi Hospital Second University of Naples (SUN), Naples, Italy., Department of Cardio-Thoracic Surgery, Thanjavur Medical College, Thanjavur, India., Division of Liver Diseases/Department of Medicine and Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.

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. 

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