Purpose of review: Recent advances have provided a model for understanding the underlying molecular genetic changes in facioscapulohumeral muscular dystrophy (FSHD). This review will highlight our current understanding and future research directions.
Recent findings: FSHD typically results from contraction of a critical number of D4Z4 repeats in a macrosatellite repeat array on chromosome 4q35. Contraction leads to loss of DNA methylation and heterochromatin markers in the 4q35 D4Z4 region, resulting in relaxation of the chromatin structure and release of DUX4 repression. DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. Stable expression of DUX4, however, can only occur in the presence of a permissive genetic background, which contains a polyadenylation signal sequence that stabilizes DUX4 mRNA. Expression of DUX4 mRNA and protein occurs at low frequency but in high abundance in FSHD myotube nuclei. DUX4 expression in transfection studies induces apoptosis and interferes with myogenesis.
Summary: FSHD results from a unique combination of genetic and epigenetic changes on 4q35 leading to release of repression of DUX4, causing disease in a toxic gain-of-function manner. Questions remain regarding the normal function of DUX4 and how expression of DUX4 in somatic cells leads to FSHD.