sdhd and sdhdh19 knockout mice do not develop paraganglioma or pheochromocytomasdhd和sdhdh19基因敲除小鼠不开发副神经节瘤或嗜铬细胞瘤.pdfVIP

Sdhd and Sdhd/H19 Knockout Mice Do Not Develop Paraganglioma or Pheochromocytoma 1 1 3 3 Jean-Pierre Bayley *, Ivonne van Minderhout , Pancras C. W. Hogendoorn , Cees J. Cornelisse , 3 3 2 2 1,3 Annemieke van der Wal , Frans A. Prins , Luc Teppema , Albert Dahan , Peter Devilee , Peter E. M. Taschner1 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands, 2 Department of Anaesthesiology, Leiden University Medical Center, Leiden, The Netherlands, 3 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands Abstract Background: Mitochondrial succinate dehydrogenase (SDH) is a component of both the tricarboxylic acid cycle and the electron transport chain. Mutations of SDHD, the first protein of intermediary metabolism shown to be involved in tumorigenesis, lead to the human tumors paraganglioma (PGL) and pheochromocytoma (PC). SDHD is remarkable in showing an ‘imprinted’ tumor suppressor phenotype. Mutations of SDHD show a very high penetrance in man and we postulated that knockout of Sdhd would lead to the development of PGL/PC, probably in aged mice. Methodology/Principal Findings: We generated a conventional knockout of Sdhd in the mouse, removing the entire third exon. We also crossed this mouse with a knockout of H19, a postulated imprinted modifier gene of Sdhd tumorigenesis, to evaluate if loss of these genes together would lead to the initiation or enhancement of tumor development. Homozygous knockout of Sdhd