Emerging preclinical animal models for FSHD

Abstract

Facioscapulohumeral dystrophy (FSHD) is a unique and complex genetic disease that is not entirely solved. Recent advances in the field have led to a consensus genetic premise for the disorder, enabling researchers to now pursue the design of preclinical models. In this review we explore all available FSHD models (DUX4-dependent and -independent) for their utility in therapeutic discovery and potential to yield novel disease insights. Owing to the complex nature of FSHD, there is currently no single model that accurately recapitulates the genetic and pathophysiological spectrum of the disorder. Existing models emphasize only specific aspects of the disease, highlighting the need for more collaborative research and novel paradigms to advance the translational research space of FSHD.

Keywords: DUX4; facioscapulohumeral dystrophy; muscular dystrophy.

Figure 1

The molecular and genetic mechanisms of FSHD type 1 and type 2. Normal, unaffected individuals carry 11–100 repeat units (triangles) within the highly condensed D4Z4 macrosatellite elements on the subtelomeric region of chromosome 4q35. Contraction of D4Z4 repeats in FSHD1 (less than 10 repeats) relaxes the chromatin structure and induces the expression of DUX4 from the distal-most repeat unit. DUX4 expressed from the non-permissive chromosomal allele without a poly(A) signal (red bar) does not become poly-adenylated and are unstable; whereas poly-adenylated DUX4 transcripts expressed from the permissive allele (green bar) are stable and translate into a toxic transcription factor, DUX4. SMCHD1 regulates D4Z4 methylation. In FSHD2, mutated SMCHD1 fails to methylate D4Z4 and to suppress DUX4 expression.