2004 Global Researcher Conference Proceeding
April 09 - 11, 2004
| Conference: | 2004 Global Researcher Conference |
|---|---|
| Title: | Long-range transcriptional regulation of the AVPR2 gene |
| Authors: | Debrand, Nicolas; Arthus, Marie-Francoise; Lonergan, Michele; Fujiwara, T. Mary; Ribes, David; Rossert, Jerome; Bichet, Daniel G. |
| Institutions: | Universite de Montreal, Hopital du Sacre-Coeur de Montreal, Montreal General Hospital, INSERM |
The primary purpose of gene control in multicellular organisms is the execution of precise development and tissue-specific decisions. As a consequence, the proper genes are expressed in the proper cells during development and differentiation. For example, the AVPR2 gene, the gene coding for the vasopressin V2 receptor, is only expressed in the kidney, in the principal cells of the collecting ducts. Transcriptional control is the primary means of regulating gene expression in eukaryotes. In eukaryotic genomes, cis-acting control elements that regulate transcription from a promoter may be located many kilobases away from the start site. We have identified a large 8 kb deletion upstream of the AVPR2 gene in one X-linked nephrogenic diabetes insipidus (NDI) family. This large deletion leaves intact the AVPR2 sequence, yet, males bearing this large deletion have classical X-linked NDI. In a second large X-linked NDI family with 6 affected males bearing a completely normal AVPR2 coding sequence, we recently identified a 102 bp deletion that is located within the 8 kb deletion of the previous family. Finally a third family with an 11 kb deletion shared the same clinical characteristics. The 102 bp region was cloned 4.6 kb upstream of the promoter region of the AVPR2 gene, and a 3-fold increase in luciferase activity was observed both in V11 cells (proximal tubules) and V47 cells (collecting ducts). A short regulatory sequence has been identified within the 102 bp region. These preliminary results are leading to a better understanding of the regulation of AVPR2 expression in human pathologies. The characterization of an optimal expression cassette capable of efficient expression of AVPR2 should be useful in the development of gene therapy for X-linked NDI.
Transcription is the process that allows information in the cell’s nucleus to move from the nucleus to the ribosomes in the cell’s cytoplasm. This is an essential part of the protein building process. In the full set of genes of an organism, the elements that control transcription may be relatively distant from the site where the gene starts to express.
Bichet, et al., discovered three NDI families that had the AVPR2 sequence of the AVPR2 gene intact, yet had a large section upstream of that sequence missing. The result is that affected males had NDI symptoms, even though their AVPR2 gene had the sequence with the necessary information to construct AVPR2 proteins.
The researchers cloned one family’s missing section of the AVPR2 gene and found an increase in a specific type of cellular activity in the cells in the proximal tubules and the collecting ducts (both of which are found in the kidney). Bichet, et al., hope that this research leads to a more complete understanding of the AVPR2 gene and thus lead to effective gene therapy for X-linked NDI.