The ter Mutation in the Rat Dnd1 Gene Initiates Gonadal Teratomas and Infertility in Both Genders

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×SPRD-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 mechanisms involved in germ cell development of both genders.

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

“…In the rat, a spontaneous mutation has been identified where a G to A substitution in exon 4 produces a premature stop codon that is thought to result in a 62 amino acid truncation at the C-terminus of the DND1 protein (Figure 1, see also [23]). This mutation leads to germ cell tumors in males and females as well as to spontaneous metastases.…”

DND1 (DND microRNA-mediated repression inhibitor 1)

“…Description DND1 contains a RNA recognition motif (RRM) through which it interacts with mRNA (Northrup et al, 2012;Weidinger et al, 2003;Youngren et al, 2005). It also has a double strand RNA binding domain (DSRM) at the C-terminus end, the function of which has not been evaluated.…”

“…Expressed in embryonic and adult germ cells, the gonads and in testicular germ cell tumors (Bhattacharya et al, 2007;Northrup et al, 2012;Weidinger et al, 2003;Youngren et al, 2005). Also expressed in other cell types such as skin and pancreas (Basu et al, 2011;Bhandari et al, 2012).…”

“…In Ter-WKY/Ztm rats, a point mutation in exon 4 of rat Dnd1 introduces a premature stop codon that likely results in expression of a C-terminus truncated DND1 protein. This results in congenital ovarian germ cell tumors (OGCTs) in females and TGCTs in males (Northrup et al, 2012). Thus DND1/Ter acts as a tumor suppressor in the rat.…”

“…Initially identified in the zebrafish, where knockdown of dnd in the early embryo resulted in loss of primordial germ cells (Weidinger et al, 2003). Mutations in Dnd1 in mice and rats, thought to result in expression of a truncated DND1 protein, are oncogenic and result in germ cell depletion as well as germ cell tumors (Youngren et al, 2005;Northrup et al, 2012). DND1 is required for the survival of primordial germ cells during early development.…”