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Genetic variation of gene expression in a rare disease of bone Osteogenesis Imperfecta (F. Jehan, V. Geoffroy)

Gene expression is subject to many factors, some of them may be due to polymorphisms in the regulatory regions of genes. These changes could explain part of the phenotypic variations observed in bone metabolism or in bone diseases such as Osteogenesis Imperfecta (OI).

Our goal is to test the functional SNPs on disease traits in a cohort of OI patients. The type of mutation in COL1A1 and COL1A2 genes (mostly haploinsufficiency or helical defects) is believed to be the main predictor of the severity of the OI phenotype. However, a high phenotypic variability between patients from the same family has been frequently shown. Our main goal is to study the impact of genetic variability on the OI phenotype, and more precisely to identify genes whose change in expression affects the severity of OI.

We have already shown an association between a polymorphism in the promoter of SOST, expression of SOST in bone and fracture incidence in OI (Domingues et al, 2011, 2012). We have identified other candidate genes such as PTHR1, OPG and RUNX2.

We will first define the relative impact of our candidate SNPs on promoter activity. These findings will then be validated in vitro and in mouse models of OI, one reproducing helical defect mutations and the other mimicking haploinsufficiency. Aiming to improve the bone phenotype of the OI mouse models, we will either use mice overexpressing or under-expressing our candidate genes. This will include mouse strains under-expressing or overexpressing SOST, which are available for purchase (KOMP repository) or in collaboration.

Finding target genes influencing fracture risk through polymorphism analysis could be of great interest in defining a more precise diagnosis and in initiating or modifying treatment. It would also help to identify new genes involved in fracture risk and therefore new potential targets for drug-based treatment, both in monogenic diseases and in more complex diseases such as osteoporosis.