title: BNP is a transcriptional target of the short stature homeobox gene SHOX.
abstract: 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 syndromes. Although much is known on the clinical and molecular aspects of SHOX haploinsufficiency, the integration of SHOX in the signalling 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.
authors: Institute of Human Genetics, Ruprecht-Karls-University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Antonio
authors: A
authors: Marchini
authors: Beate
authors: B
authors: Häcker
authors: Tiina
authors: T
authors: Marttila
authors: Volker
authors: V
authors: Hesse
authors: Joyce
authors: J
authors: Emons
authors: Birgit
authors: B
authors: Weiss
authors: Marcel
authors: M
authors: Karperien
authors: Gudrun
authors: G
authors: Rappold
mesh_terms: D000293:Adolescent; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000378:metabolism; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020097:Natriuretic Peptide, Brain / Q000235:genetics* / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology; D020218:Response Elements; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D020097:Natriuretic Peptide, Brain