Osteoporosis and other Bone phenotypes

We collaborate with european/international groups gathered in the GEFOS-GENOMOS consortium and in the GEMSTONE COST action. Recently, we have studied genes/variants associated with osteoporosis or non-pathogenic high bone mass (HBM), including WNT16, DKK1 and SOST, and have undertaken functional analyses at cellular level as well as 4C conformation capture experiments to investigate regulation of these genes in bone cells.  We have also functionally studied the C7ORF67 locus, a gene containing a SNP strongly associated with bone mineral density (BMD), and a putative osteoblast enhancer within it, by disrupting it with CRISPR/Cas9 in a mouse model, and then performing 4C experiments and testing the enhancer sequence in luciferase reporter experiments.

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We are interested in the genetic background of atypical femoral fracture (AFF) cases related to long-term osteoporosis treatment with bisphosphonates (BPs). We identified and - through a collaboration with colleagues form UK and USA - functionally characterized a rare missense variant in GGPS1 shared by 3 affected sisters. We also functionally tested variants of CYP1A1 found in independent AFF cases and performed exome sequencing in a small cohort of Spanish AFF cases.  

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We undertake massive sequencing approaches to familial cases of HBM and a scrutiny of osteogenesis imperfecta (OI) genes in women diagnosed with osteoporosis, to assess the degree of gene/variant sharing between these two clinical entities.

Whenever appropriate, we undertake functional analyses of the most suggestive variants uncovered by these screens, through cell based in vitro approaches. In particular, we are currently following up on the effect of variants in LRP6, SEMA4D and TBX18.

 

As a side project, we have investigated evolutionary aspects of LRP5, an important BMD-determining gene, by functionally testing specific Neanderthal and Denisovan missense variants and relating their enhanced activity to the skeletal robustness of these extinct hominins.