the ter mutation in the rat dnd1 gene initiates gonadal teratomas and infertility in both genderster突变鼠dnd1基因启动性腺的畸胎瘤,男女不孕不育.pdfVIP

The ter Mutation in the Rat Dnd1 Gene Initiates Gonadal Teratomas and Infertility in Both Genders 1 . 1. ¨ 1 1 1 Emily Northrup * , Nils-Holger Zschemisch , Regina Eisenblatter , Silke Glage , Dirk Wedekind , 2 1 ¨ 1 Edwin Cuppen , Martina Dorsch , Hans-Jurgen Hedrich 1 Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany, 2 Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands Abstract A spontaneous mutation leading to the formation of congenital ovarian and testicular tumors was detected in the WKY/Ztm rat strain. The histological evaluation revealed derivatives from all three germ layers, thereby identifying these tumors as teratomas. Teratocarcinogenesis was accompanied by infertility and the underlying mutation was termed ter. Linkage analysis of 58 (WKY-ter 6SPRD-Cu3) F2 rats associated the ter mutation with RNO18 (LOD = 3.25). Sequencing of candidate genes detected a point mutation in exon 4 of the dead-end homolog 1 gene (Dnd1), which introduces a premature stop codon assumed to cause a truncation of the Dnd1 protein. Genotyping of the recessive ter mutation revealed a complete penetrance of teratocarcinogenesis and infertility in homozygous ter rats of both genders. Morphologically non-tumorous testes of homozygous ter males were reduced in both size and weight. This testicular malformation was linked to a lack of spermatogenesis using immunohistochemical and histological staining. Our WKY-Dnd1ter/Ztm rat is a novel animal model to investigate gonadal teratocarcinogenesis and the molecular me