Paget's disease of bone (PDB) is the second most prevalent bone disorder, affecting 2-5% of Caucasian individuals >55 years of age. PDB is caused by defects in the bone-resorbing osteoclasts which become hyperactive, leading to focal skeletal lesions. For a minority of cases, a clear genetic cause has been identified. Mutations in the sequestosome 1 (SQSTM1) gene can be found in 20% of patients and account for 50% of familial cases. Recent genetic studies led to the association of 7 loci with PDB. Several genes found at these loci are involved in NF-kB signaling. We looked for variation in the genes that encode different components of the pathway in PDB patients, and identified interesting variants in the CBL, CBLB and NR4A1 genes. These genes act as a break on osteoclast formation and activity. We aim to validate disease causality by modeling the variants in zebrafish. As a proof of concept, SQSTM1 mutant fish is being generated as a potential first zebrafish model for Paget’s disease of bone.
Bone metabolism is a complex process which is not only important during the development of the skeleton with the regulation of bone growth but also throughout life to maintain bone mass and bone strength. In our research group, we investigate the genetic cause of several skeletal dysplasias marked by abnormal bone mass or growth. In the past, this already resulted in the identification of several disease causing genes. In this study, we aim to identify the genetic causes in unsolved high bone mass patients by whole exome and genome sequencing. To validate the causality of variants in vitro functional studies are performed.
PhD student: Yentl Huybrechts
Promotors: Wim Van Hul, Geert Mortier, Gretl Hendrickx & Eveline Boudin
