WNT Signaling, Skeletal Development & Cancer

Osteopathia striata congenita with cranial sclerosis (OSCS) 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 the skeletal manifestations, but also multiple, often life-limiting, malformations in multiple organ systems. In 2008 members of the Clinical Genetics Research Group identified mutations in a gene called WTX as the cause of OSCS. 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 childhood kidney cancer, Wilms tumour. 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 multiple malformations in several organ systems.