Human Molecular Genetics Advance Access published online on September 19, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm266
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BNP is a transcriptional target of the short stature homeobox gene SHOX
1 Institute of Human Genetics, Ruprecht-Karls-University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany 2 Present address: German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany 3 Department of Pediatrics, Sana Klinikum Lichtenberg, Gotlindestrasse 2-20, 10356 Berlin Germany 4 Departments of Pediatrics and Endocrinology and Metabolic Diseases, Leiden University Medical Center, P. O. Box 9600, 2300 RC Leiden, The Netherlands
* To whom correspondence should be addressed at: Institute of Human Genetics, Ruprecht-Karls-University at Heidelberg, Im Neuenheimer Feld 366, 69120 eidelberg, Germany. Tel: +49-6221-56-5059. Fax: +49-6221-56-5332. E-mail: gudrun_rappold{at}med.uni-heidelberg.de
Received July 27, 2007; Revised September 6, 2007; Accepted September 16, 2007
Short stature due to SHOX deficiency represents a common congenital form of growth failure and is involved in the aetiology of "idiopathic" short stature and the growth deficits and skeletal anomalies in Leri Weill, Langer and Turner syndrome. While much is known on the clinical and molecular aspects of SHOX haploinsufficiency, the integration of SHOX in the signaling pathways regulating bone growth is currently not defined. Here we identify NPPB encoding the natriuretic peptide BNP, a well known cardiac and natriuretic peptide hormone, as a transcriptional target of SHOX. The ability of SHOX to transactivate the NPPB endogenous promoter was demonstrated in luciferase reporter assays using serial deletions of the NPPB promotor region. Binding of SHOX to the NPPB promoter was also demonstrated in vivo by chromatin fixation and immunoprecipitation. We also demonstrate the lack of promoter activation in two SHOX mutants from patients with Leri-Weill syndrome. In addition, immunohistochemical analysis of human growth plate sections showed for the first time a co-expression of BNP and SHOX in late proliferative and hypertrophic chondrocytes. Together these data strongly suggest that BNP represents a direct target of SHOX.
The first two authors have contributed equally to this work
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