Human Molecular Genetics, 2002, Vol. 11, No. 6 641-649
© 2002 Oxford University Press
Disruption of a novel MFS transporter gene, DIRC2, by a familial renal cell carcinoma-associated t(2;3)(q35;q21)
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands, 1Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer and Development Center, Frederick, MD 21702 USA and 2Urologic Oncology Section Surgery Branch, National Institute of Health, Bethesda, MD 20892, USA
Previously, we described a family with a significantly increased predisposition for renal cell cancer co-segregating with a t(2;3)(q35;q21) chromosomal translocation. Several primary tumors of the clear cell type from different family members were analyzed at a molecular level. Loss of the derivative chromosome 3 was consistently found. In addition, different somatic Von Hippel Lindau (VHL) gene mutations were observed in most of the tumors analyzed, even within the same patient. Based on these results a multistep tumorigenesis model was proposed in which (non-disjunctional) loss of the derivative chromosome 3 represents an early event and somatic mutation of the VHL gene represents a late event related to tumor progression. More recently, however, we noted that these two anomalies were absent in at least one early-stage tumor sample that we tested. Similar results were obtained in another family with renal cell cancer and t(3;6)(q12;q15), thus suggesting that another genetic event may precede these two oncogenetic steps. We speculate that deregulation of a gene(s) located at or near the translocation breakpoint may act as such. In order to identify such genes, a detailed physical map encompassing the 3q21 breakpoint region was constructed. Through a subsequent positional cloning effort we found that this breakpoint targets a hitherto unidentified gene, designated DIRC2 (disrupted in renal cancer 2). Computer predictions of the putative DIRC2 protein showed significant homology to different members of the major facilitator superfamily (MFS) of transporters. Based on additional DIRC2 expression and mutation analyses, we propose that the observed gene disruption may result in haplo-insufficiency and, through this mechanism, in the onset of tumor growth.
+ To whom correspondence should be addressed. Tel: +31 24 3618847; Fax: +31 24 3540488; Email: d.bodmer@antrg.azn.nl Present address:Marian Weterman, Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y.-S. Kim, H. S. Kang, R. Herbert, J. Y. Beak, J. B. Collins, S. F. Grissom, and A. M. Jetten Kruppel-Like Zinc Finger Protein Glis2 Is Essential for the Maintenance of Normal Renal Functions Mol. Cell. Biol., April 1, 2008; 28(7): 2358 - 2367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rodriguez-Perales, B. Melendez, S. M. Gribble, L. Valle, N. P. Carter, I. Santamaria, L. Conde, M. Urioste, J. Benitez, and J. C. Cigudosa Cloning of a new familial t(3;8) translocation associated with conventional renal cell carcinoma reveals a 5 kb microdeletion and no gene involved in the rearrangement Hum. Mol. Genet., May 1, 2004; 13(9): 983 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Bodmer, W. van den Hurk, J. J. M. van Groningen, M. J. Eleveld, G. J. M. Martens, M. A. J. Weterman, and A. Geurts van Kessel Understanding familial and non-familial renal cell cancer Hum. Mol. Genet., October 1, 2002; 11(20): 2489 - 2498. [Abstract] [Full Text] [PDF]
|
|