The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours

Nature. 2005 May 19;435(7040):360-4. doi: 10.1038/nature03595.


In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells, and after birth differentiate into various cells and tissues that compose TGCTs. Here, we report the positional cloning of Ter, revealing a point mutation that introduces a termination codon in the mouse orthologue (Dnd1) of the zebrafish dead end (dnd) gene. PGC deficiency is corrected both with bacterial artificial chromosomes that contain Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal gonads during the critical period when TGCTs originate. DND1 has an RNA recognition motif and is most similar to the apobec complementation factor, a component of the cytidine to uridine RNA-editing complex. These results suggest that Ter may adversely affect essential aspects of RNA biology during PGC development. DND1 is the first protein known to have an RNA recognition motif directly implicated as a heritable cause of spontaneous tumorigenesis. TGCT development in the 129-Ter mouse strain models paediatric TGCT in humans. This work will have important implications for our understanding of the genetic control of TGCT pathogenesis and PGC biology.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Base Sequence
  • Body Weight
  • Chromosome Mapping
  • Chromosomes, Mammalian / genetics
  • Disease Models, Animal
  • Gene Expression Profiling
  • Genetic Complementation Test
  • Germ Cells / metabolism*
  • Germ Cells / pathology*
  • In Situ Hybridization
  • Male
  • Mice
  • Mutation / genetics*
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Organ Size
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Testicular Neoplasms / genetics*
  • Testicular Neoplasms / metabolism
  • Testicular Neoplasms / pathology*
  • Testis / embryology
  • Testis / metabolism
  • Testis / pathology


  • Dnd1 protein, mouse
  • Neoplasm Proteins
  • RNA, Messenger