Sclerosing bone dysplasias
Background
Osteoporosis is the most common metabolic bone disorder, characterized by a decreased bone mass resulting in an increased fracture risk. It is a multifactorial disease with environmental factors contributing but also the heritability is high, indicating an important role for genetic factors. In the last decade, a lot of novel genes and associated pathogenic mechanisms have been identified by studying monogenic conditions with an abnormal bone mass. These include the sclerosing bone dysplasias in which patients have an increased bone mass.
Goal
We aim to identify novel genes and genetic variants that are causal for increased bone mass in monogenic sclerosing bone dysplasias. The unravelling of these pathogenic mechanisms is of relevance for the patients but could also result in gained insights into the homeostasis of bone mass in the general population and in patients diagnosed with osteoporosis.
Strategy
DNA sequencing is performed on DNA from patients with an abnormal bone mass. The approach can range between sequencing candidate genes, the use of a (virtual) gene panel or whole exome of genome sequencing. Genetic variants of potential relevance are validated by in vitro functional studies or by construction and phenotyping of animal models including mouse and zebrafish models.
Disorders under investigation
Team Members
- Bone disease research (PhD Yentl Huybrechts - defended 2023)
Identification of the underlying mechanism whereby Sclerostin and Gremlin1 regulate canonical WNT signalling and bone formation.
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
Team members - Hereditary bone disorders
Wim Van Hul
Wim Van Hul
Ellen Steenackers
Lab technicianEllen Steenackers
Lab technician