Identification of novel genetic markers
Dr Omar Albagha and his team from the Institute of Genetics and Molecular Medicine, at the University of Edinburgh, were awarded a grant by the Paget’s Association to support research which will improve our understanding of the biology of Paget’s disease. [2017-2021]
We have known for some time that genetics play an important role in susceptibility to Paget’s, for example, with the SQSTM1 gene playing a central role, but the precise genes involved have alluded researchers
New Paget’s Gene found
Paget’s Disease of Bone often runs in families and sometimes can be passed on from one generation to the next. Until relatively recently very little was known about the genetic characteristics of patients with Paget’s disease and because of this, it was almost impossible to predict if the disease would be passed on from parent to child. There have been huge advances in understanding exactly which genetic factors are associated with the development of Paget’s disease. Over the past 15 years, however, huge advances have been made in identifying the gene abnormalities, which occur in the condition. So far, about 8 gene variants that predispose to Paget’s disease have been discovered, but research indicates that there are other variants that remain to be identified.
The aim of this project was to identify new genetic variants, which predispose to Paget’s disease using a technique called, A Genome Wide Association Study. The study built upon work that has already been performed, with the aim of providing a comprehensive picture, of which genetic variants predispose to the condition. The value of the project is that it allowed the researchers to develop accurate genetic markers for Paget’s disease that could be offered to people who have a family history of the disease and provide information whether they are likely to develop it themselves, in future years. People who were found to have markers suggestive of developing Paget’s disease could be entered into a programme of enhanced surveillance so that the disease could be picked up early and they could be offered preventative therapy.
The study confirmed that a new Paget’s gene called ‘PML’ controls the biology of osteoclasts and osteoblasts, bone cells that are central to Paget’s disease.
We have known for some time that genetics play an important role in susceptibility to Paget’s, for example, with the SQSTM1 gene playing a central role, but the precise genes involved have alluded researchers. In their research, Wani and co-workers have pinned down one such new gene, termed PML. By analysing blood samples from those living with Paget’s disease, the team found that an alteration in the PML gene causes less of the PML protein to be made. This alteration is found in people with Paget's but not in individuals without signs of Paget’s.
Further experiments showed that reducing levels of the PML protein is associated with increased bone turnover, a feature of Paget's, consistent with the genetic alteration being important in the disease. Improved knowledge of Paget’s genetics may help direct future clinical management.
Reference: Wani S., Daroszewska A., Salter D.M., van ’t Hof, R., Ralston, S.H. and Albagha, O.M.E. (2022). Reduced expression of PML predisposes to Paget’s disease of bone by increasing osteoclast differentiation and bone resorption. Disease Models & Mechanisms. Mar 1. Epub ahead of print.