A protein called DUX4, incorrectly expressed in skeletal muscle fibres, is emerging as a major factor in facioscapulohumeral muscular dystrophy (FSHD). In FSHD-affected muscles, full-length DUX4 protein disrupts numerous biochemical processes and appears to inhibit the survival and regeneration of skeletal muscle fibres. Stephen Tapscott, a neurologist and molecular geneticist at the Fred Hutchinson Cancer Research Center in Seattle, was recently interviewed about the DUX4 findings and what they may mean for the FSHD community. He explains why targeting DUX4 and its downstream effects is a promising therapeutic avenue for the treatment of FSHD. In this podcast, Stephen Tapscott describes how a mutation on chromosome 4, in which repeated sequences of DNA are deleted, was identified two decades ago as the root cause of FSHD. Since then, many research groups have tried to identify the mechanism by which this deletion leads to loss of muscle tissue in FSHD. Misregulation of the DUX4 gene and inappropriate expression of the DUX4 protein were proposed early on as possible causes of FSHD, but until recently, the technology wasn't sufficient to demonstrate their involvement. It's now clear that the loss of some of the repeated DNA units on chromosome 4 causes the expression of the DUX4 protein in skeletal muscle tissue, where it's not normally expressed. The presence of DUX4 in skeletal muscle tissue may cause the death of muscle cells via a cell death program known as apoptosis. It also may cause the immune system to attack muscle fibres, and activate proteins that block normal muscle regeneration.