1. Department of Genetics and
2. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA
3. Department of Cell Biology, Duke University, Durham, North Carolina 27710, USA
4. Department of Molecular Genetics, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
5. Basic Research Program, SAIC-Frederick, Inc., and
6. Laboratory of Immunobiology, NCI Frederick, Frederick, Maryland 21702, USA
7. Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA

Correspondence to: Joseph H. Nadeau^1,2Angabin Matin⁴ Correspondence and requests for materials should be addressed to A.M. (Email: amatin@mdanderson.org) or J.H.N. (Email: jhn4@case.edu).

Abstract

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds¹. 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^{2, 3, 4}. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells^{2, 3, 4, 5, 6}, 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.

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