In 2008, members of the Clinical Genetics Group identified mutations in a gene called WTX as the cause of osteopathia striata congenita with cranial sclerosis (OSCS). This is an X-linked dominant disorder characterized by the accrual of dense, sclerotic bone throughout the skeleton, most especially the skull. Males who are hemizygous for a disease-causing mutation are severely affected—not only with skeletal manifestations, but also with malformations in multiple organ systems, which are often life-limiting.
Several surprising aspects have arisen out of this discovery. For instance, WTX is a negative regulator of WNT signaling and it has also been shown to be a tumour suppressor gene, implicated in the development of Wilms tumour, a kidney cancer which primarily affects children. Ongoing work in the laboratory is aimed at disentangling this developmental disease-cancer link in addition to addressing questions around how defects in WNT signaling can cause such widespread malformations in several organ systems.
Additionally, a variety of other sclerosing bone dysplasias have been under study in the lab, including disorders caused by defects in other components of the WNT signaling pathway and in retinoic acid metabolism.
Funded by Cure Kids, HRC, and the Marsden Fund