G.I.1 New advances in facioscapulohumeral dystrophy

Abstract

Recent advances in our understanding of the genetic basis of facioscapulohumeral dystrophy (FSHD) has provided a uniform disease mechanism in which FSHD is caused by partial chromatin opening of the D4Z4 repeat array on chromosome 4 and variegated expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In the common form FSHD1, the epigenetic changes in D4Z4 are caused by contraction of the D4Z4 repeat array to a size of 1–10units. In the rare form FSHD2, D4Z4 chromatin relaxation and somatic DUX4 expression is caused by mutations in SMCHD1 on chromosome 18. Our studies also provide evidence that SMCHD1 can act as a modifier of disease severity in FSHD1. SMCHD1 is a chromatin modifier that binds directly to the D4Z4 repeat array to maintain a repressive chromatin structure in somatic cells. In FSHD2 patients we observed reduced binding of SMCHD1 to D4Z4 and SMCHD1 reduction by RNA interference in normal myoblasts activates DUX4 expression. Our data thus suggest that the disease mechanisms of FSHD1 and FSHD2 converge at the level of D4Z4 chromatin opening and somatic DUX4 expression. The epigenetic regulation of the D4Z4 repeat is evolutionary conserved as we can accurately model the D4Z4 chromatin structure of normal and disease alleles in transgenic mouse models. These mouse models are expected to become valuable tools for the identification of therapeutic molecules that suppress DUX4 expression in muscle.