IP: Dra. Karen E. Heath

Resumen del proyecto: SHOX (short stature homeobox-containing gene), located in the pseudoautosomal region (PAR1) of the short arm of the X and Y chromosomes, encodes a homeodomain transcription factor involved in human skeletal growth. SHOX haploinsuficiency has been demonstrated in Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), two skeletal dysplasias associated with disproportionate short stature, as well as in a variable proportion of cases with idiopathic short stature (ISS), thus suggesting that SHOX plays an important role in human skeletal growth.
Previous work by others, identified SHOX mutations in only 40-70% of LWD cases whilst no molecular defect was detected in the remaining 30-60%. In 2003, we proposed that alternative regions of PAR1 or other genes could be implicated in these pathologies. In the following years we reported on the identification of a novel class of PAR1 deletions downstream of SHOX in LWD patients (Benito-Sanz et al. 2005; 2006ab; Campos-Barros et al. 2007) where SHOX enhancers have now been identified. More recently, we have also detected a significantly higher incidence of small deletions within this region in ISS cases but the pathogenicity of these alterations is currently under investigation (Benito-Sanz et al, 2011a). Furthermore, our recent investigations have led to the identification of partial and complete SHOX duplications in LWD patients (Benito-Sanz et al, 2011b). Though our work has contributed to improve the molecular diagnosis of LWD, LMD and ISS cases there are still patients without a known molecular defect.
Despite the relatively large amount of information regarding SHOX gathered during the last decade, the molecular pathogenetic mechanism of SHOX mutations in the described syndromes is still not well understood. For this reason in 2006, we set out to investigate the signalling pathways in which SHOX is involved by the identification of SHOX transcription targets and SHOX interacting proteins (Aza-Carmona et al, 2011). Therefore, this project is aimed to continue to investigate the pathophysiological mechanisms by which SHOX regulates human growth and skeletal development.

Entidad financiadora: Ministerio de Ciencia e Innovación