Researchers from the Faculty of Health Sciences, National Institute of Biotechnology in the Negev and Soroka University Medical Center have identified a gene defect which sheds new light on mineral loss in bones. Their research was recently published in the American Journal of Human Genetics (AJHG).

Studying rare extreme forms of common disease lays the foundation for identifying the mechanisms that underlie the more common forms of the disease. Studies in rare bone diseases with an inheritance pattern that can be attributed to a defect in a single gene have proven their potential to identify several previously unknown genes that play key roles in regulating bone mass and bone turnover.

Prof. Eli Hershkovitz and Dr. Neta Leventhal from the Pediatric Endocrinology & Metabolism Unit in Soroka University Medical Center and the Faculty of Health Sciences characterized an enlarged consanguineous Bedouin family of hypophosphatemic rickets with such an inheritance pattern. Further research in the group of Prof. Ruti Parvari of the Department of Developmental Genetics and Virology and National Institute of Biotechnology in the Negev by Luba Avizov, an M.Sc. student, identified the chromosomal location of the gene. Varda Levi-Litan, an M.D. Ph.D. student, identified the mutation and with the help of Prof. J. Goding from Australia the group further succeeded to demonstrate that the mutation causes loss of function of the gene. This result was surprising since previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, mainly generalized arterial calcifications leading to death at infancy, whereas no aberrant calcifications were present in our patients

The identification of the gene contributes to better understanding of phosphate homeostasis and possible intervening in the pathological situations of reduced BMD and osteoporosis. Future research is directed at verification of the contribution of natural occurring changes in this gene to bone mineral density in the general population and elucidating the novel pathway involved in the generation of rickets and possible additional functions for the gene.

Osteoporosis affects nearly 45 million postmenopausal women worldwide with fracture rates that far exceed the combined incidence of breast cancer, stroke and heart attacks. Bone mineral density (BMD) is the major determinant of osteoporotic fracture risk and has a strong genetic component.  Many different genetic variants of modest effect are likely to contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Although there has been extensive progress in identifying the genetic variants that regulate bone mass and susceptibility to osteoporosis, it is assumed that most of these remain to be discovered. Bone contains approximately 85% of the total body phosphate but despite its broad biological importance the control of phosphour homeostasis is only partly understood. Only 3 genes were identified as crucial for phosphate homeostasis and it is suggested that additional factors are yet to be identified.