title: The Leri-Weill and Turner syndrome homeobox gene SHOX encodes a cell-type specific transcriptional activator.
abstract: Functional impairment of the human homeobox gene SHOX causes short stature and Madelung deformity in Leri-Weill syndrome (LWS) and has recently been implicated in additional skeletal malformations frequently observed in Turner syndrome. To enhance our understanding of the underlying mechanism of action, we have established a cell culture model consisting of four stably transfected cell lines and analysed the functional properties of the SHOX protein on a molecular level. Results show that the SHOX-encoded protein is located exclusively within the nucleus of a variety of cell lines, including U2Os, HEK293, COS7 and NIH 3T3 cells. In contrast to this cell-type independent nuclear translocation, the transactivating potential of the SHOX protein on different luciferase reporter constructs was observed only in the osteogenic cell line U2Os. Since C-terminally truncated forms of SHOX lead to LWS and idiopathic short stature, we have compared the activity of wild-type and truncated SHOX proteins. Interestingly, C-terminally truncated SHOX proteins are inactive with regards to target gene activation. These results for the first time provide an explanation of SHOX-related phenotypes on a molecular level and suggest the existence of qualitative trait loci modulating SHOX activity in a cell-type specific manner.
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Rao
authors.forename: R J
authors.initials: RJ
authors.lastname: Blaschke
authors.forename: A
authors.initials: A
authors.lastname: Marchini
authors.forename: B
authors.initials: B
authors.lastname: Niesler
authors.forename: M
authors.initials: M
authors.lastname: Burnett
authors.forename: G A
authors.initials: GA
authors.lastname: Rappold
mesh_terms: D015153:Blotting, Western; D001827:Body Height; D002460:Cell Line; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000074122:Short Stature Homeobox Protein; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology; D014424:Turner Syndrome / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D020798:Two-Hybrid System Techniques
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D015534:Trans-Activators