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Margo Dona Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Selma Waaijers Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Susan Richter Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany

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Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
Department of Medicine ΙΙΙ, University Hospital Dresden, Dresden, Germany

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Jeroen Korving Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands

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Sarah M Kamel Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands

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Jeroen Bakkers Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
Division of Heart and Lungs, Department of Medical Physiology, UMC Utrecht, Utrecht, the Netherlands

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Elena Rapizzi Department of Biomedical, Experimental and Clinical Sciences ‘Mario Serio’, University of Florence, Firenze, Italy

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Richard J Rodenburg Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, the Netherlands

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Jan Zethof Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Marnix Gorissen Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Gert Flik Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Peter M T Deen Radboud University, Nijmegen, the Netherlands

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Henri J L M Timmers Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Pheochromocytomas and paragangliomas (PPGLs) caused by mutations in the B-subunit of the succinate dehydrogenase (SDHB) have the highest metastatic rate among PPGLs, and effective systemic therapy is lacking. To unravel underlying pathogenic mechanisms, and to evaluate therapeutic strategies, suitable in vivo models are needed. The available systemic Sdhb knock-out mice cannot model the human PPGL phenotype: heterozygous Sdhb mice lack a disease phenotype, and homozygous Sdhb mice are embryonically lethal. Using CRISPR/cas9 technology, we introduced a protein-truncating germline lesion into the zebrafish sdhb gene. Heterozygous sdhb mutants were viable and displayed no obvious morphological or developmental defects. Homozygous sdhb larvae were viable, but exhibited a decreased lifespan. Morphological analysis revealed incompletely or non-inflated swim bladders in homozygous sdhb mutants at day 6. Although no differences in number and ultrastructure of the mitochondria were observed. Clear defects in energy metabolism and swimming behavior were observed in homozygous sdhb mutant larvae. Functional and metabolomic analyses revealed decreased mitochondrial complex 2 activity and significant succinate accumulation in the homozygous sdhb mutant larvae, mimicking the metabolic effects observed in SDHB-associated PPGLs. This is the first study to present a vertebrate animal model that mimics metabolic effects of SDHB-associated PPGLs. This model will be useful in unraveling pathomechanisms behind SDHB-associated PPGLs. We can now study the metabolic effects of sdhb disruption during different developmental stages and develop screening assays to identify novel therapeutic targets in vivo. Besides oncological syndromes, our model might also be useful for pediatric mitochondrial disease caused by loss of the SDHB gene.

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