An international team of scientists led by geneticist Dr Anne Hughes at the Queens University of Belfast, molecular biologist Dr Dirk Anderson, of Immunex (Nasdaq: IMNX) in Seattle, and bone specialist Professor Stuart Ralston, of the University of Aberdeen, have identified the gene responsible for Familial Expansile Osteolysis - a severe form of Paget's disease of bone.
The discovery, published in the January 2000 issue of Nature Genetics, is a major advance in understanding the cause of the enigmatic disease, which causes bone pain and bone deformity and which is sometimes so severe as to require amputation.
Identification of the gene that causes FEO is a major advance in understanding how bone metabolism is controlled.
Professor Ralston, who in 1996 led the team which discovered a simple genetic test to help identify those vulnerable to osteoporosis, another crippling bone disease, said: “This discovery is of great scientific interest and will also be of clinical value in identifying individuals from these families who are destined to develop the disease before it has become advanced, so that preventative treatment can be given at an early stage.
“It also opens up the possibility that we may be able to develop new treatments for the disease by using drugs that specifically target the faulty gene.”
The Belfast and Aberdeen-based research groups became interested in the role of genetic factors as a cause of the disease when they came across families where bone disease had been inherited from one generation to the next, affecting individuals from their teenage years and early 20s.
Work by Dr Hughes’s research group in Belfast first demonstrated that the gene responsible for FEO was located near the bottom of chromosome 18 and studies by the Aberdeen group, led by Professor Ralston, showed that in some cases, the closely-related condition, familial Paget’s disease of Bone, were caused by a gene located in the same region.
Independently, an Immunex team of scientists, led by Dr Anderson, had identified a gene in the same part of chromosome 18 that encodes the RANK protein, an important regulator of bone metabolism.
Collaborative research conducted by the researchers in Aberdeen, Belfast and Seattle then defined the organisation of the RANK gene and characterised the mutations responsible for the disease, along with other researchers in the US, Japan, Germany and Belgium. Mutations involving the duplication of 18 bases in the DNA sequence were found in people with FEO who were members of unrelated families from Northern Ireland, the US and Germany. A similar, but slightly larger duplication of 27 bases was discovered in one family with a familial form of Paget’s disease of bone.
The studies described in Nature Genetics showed that mutations in the RANK gene were responsible for the disease in affected individuals from 4 families. The gene is known to play a crucial role in the development of cells responsible for bone remodelling.
Dr Dirk Anderson of Immunex said: “Identifying the specific gene that is responsible for a disease is relatively rare and this collaborative work was the key to our success. Combining the genetic understanding of FEO and RANK with our knowledge of RANK and its role in regulating bone metabolism allowed us to identify the RANK gene as the defective gene in these individuals.”
The National Association funded the work on collecting families and mapping of Paget’s for Relief of Paget’s Disease (NARPD), the ARC and the Wellcome Trust at various points.