title: Recessive transmission of a multiple endocrine neoplasia syndrome in the rat.
abstract: We describe a novel hereditary cancer syndrome in the rat that is transmitted by a recessive gene mutation. Animals exhibiting the mutant phenotype develop multiple neuroendocrine malignancies within the first year of life. The endocrine neoplasia is characterized by bilateral adrenal pheochromocytoma, multiple extra-adrenal pheochromocytoma, bilateral medullary thyroid cell neoplasia, bilateral parathyroid hyperplasia, and pituitary adenoma. The appearance of neoplastic disease is preceded by the development of bilateral juvenile cataracts. Although the spectrum of affected tissues is reminiscent of human forms of multiple endocrine neoplasia (MEN), no germ-line mutations were detected in the Ret or Menin genes that are responsible for the dominantly inherited MEN syndromes in humans. Segregation studies in F1 and F2 crosses yielded frequencies of affected animals entirely consistent with a recessive autosomal mode of inheritance. The lack of the phenotype in F1 animals effectively excludes a germ-line tumor suppressor gene mutation as the causal event. The absence of mutation of known MEN genes and the unique constellation of affected tissues, plus the recessive mode of inheritance, lead us to conclude that the mutation of an as yet unknown gene is responsible for this syndrome of inherited neuroendocrine cancer.
authors.affiliation: Institute of Pathology, GSF-National Research Center for Environment and Health, Ingolstaedter Landstrasse 1, D-85764 Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritz
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Kamilla
authors.initials: K
authors.lastname: Piotrowska
authors.forename: Michael
authors.initials: M
authors.lastname: Rosemann
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schäffer
authors.forename: Karin
authors.initials: K
authors.lastname: Weber
authors.forename: Andreas
authors.initials: A
authors.lastname: Timper
authors.forename: Gerhild
authors.initials: G
authors.lastname: Wildner
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D029721:Drosophila Proteins; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D018095:Germ-Line Mutation; D008297:Male; D009377:Multiple Endocrine Neoplasia / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat