RAF1 mutations in childhood-onset dilated cardiomyopathy.
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.
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.
Perundurai S
PS
Dhandapany
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Md Abdur
MA
Razzaque
Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India.
Uthiralingam
U
Muthusami
Department of Advanced Zoology and Biotechnology, Loyola College, Chennai, India.
Sreejith
S
Kunnoth
The Mindich Child Health and Development Institute, Hess Center for Science and Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Jonathan J
JJ
Edwards
The Mindich Child Health and Development Institute, Hess Center for Science and Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Sonia
S
Mulero-Navarro
The Mindich Child Health and Development Institute, Hess Center for Science and Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Ilan
I
Riess
Recinto de Ciencias Médicas, Universidad de Puerto Rico, San Juan, Puerto Rico.
Sherly
S
Pardo
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Jipo
J
Sheng
Center for Cellular and Molecular Biology, Hyderabad, India.
Deepa Selvi
DS
Rani
Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Bindhu
B
Rani
Department of Biomedical Science, School of Basic Medical Sciences, Bharathidasan University, Tiruchirappalli, India.
Periyasamy
P
Govindaraj
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Elisabetta
E
Flex
International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
Tomohiro
T
Yokota
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.
Michiko
M
Furutani
International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan.
Tsutomu
T
Nishizawa
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.
Toshio
T
Nakanishi
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Jeffrey
J
Robbins
Monaldi Hospital Second University of Naples (SUN), Naples, Italy.
Giuseppe
G
Limongelli
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Roger J
RJ
Hajjar
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, USA.
Djamel
D
Lebeche
Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Ajay
A
Bahl
Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Madhu
M
Khullar
Department of Cardio-Thoracic Surgery, Thanjavur Medical College, Thanjavur, India.
Andiappan
A
Rathinavel
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.
Kirsten C
KC
Sadler
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
Marco
M
Tartaglia
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.
Rumiko
R
Matsuoka
Center for Cellular and Molecular Biology, Hyderabad, India.
Kumarasamy
K
Thangaraj
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.
Bruce D
BD
Gelb
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007194:India; D007564:Japan; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D020123:Sirolimus / Q000737:chemistry; D015027:Zebrafish
D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus