title: Sdhd and SDHD/H19 knockout mice do not develop paraganglioma or pheochromocytoma.
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.
  
  
  RESULTS
  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 results in embryonic lethality. No paraganglioma or other tumor development was seen in Sdhd KO mice followed for their entire lifespan, in sharp contrast to the highly penetrant phenotype in humans. Heterozygous Sdhd KO mice did not show hyperplasia of paraganglioma-related tissues such as the carotid body or of the adrenal medulla, or any genotype-related pathology, with similar body and organ weights to wildtype mice. A cohort of Sdhd/H19 KO mice developed several cases of profound cardiac hypertrophy, but showed no evidence of PGL/PC.
  
  
  CONCLUSIONS
  Knockout of Sdhd in the mouse does not result in a disease phenotype. H19 may not be an initiator of PGL/PC tumorigenesis.
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. j.p.l.bayley@lumc.nl
authors: Jean-Pierre
authors: JP
authors: Bayley
authors: Ivonne
authors: I
authors: van Minderhout
authors: Pancras C W
authors: PC
authors: Hogendoorn
authors: Cees J
authors: CJ
authors: Cornelisse
authors: Annemieke
authors: A
authors: van der Wal
authors: Frans A
authors: FA
authors: Prins
authors: Luc
authors: L
authors: Teppema
authors: Albert
authors: A
authors: Dahan
authors: Peter
authors: P
authors: Devilee
authors: Peter E M
authors: PE
authors: Taschner
mesh_terms: D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics*; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D013385:Succinate Dehydrogenase