FSHD: Modifiers of SMCHD1 expression

Background
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disease for which no cure is available. FSHD is caused by the toxic expression of the transcription factor DUX4 in skeletal muscle. In skeletal muscle, DUX4 expression is regulated by several factors, of which one of the key factors in preventing DUX4 expression is SMCHD1. In fact, haplo-insufficient SMCHD1 mutations are the major cause of FSHD2. Interestingly, we have previously shown that increased levels of SMCHD1 can reduce expression of DUX4 in FSHD-affected cells. This makes SMCHD1 an interesting therapeutic target for FSHD. In this project we study the mechanisms that govern SMCHD1 levels in muscle cells, with the aim to develop an SMCHD1-centered therapy for FSHD.

Methods
We use patient-derived (muscle) cell lines and state-of-the-art molecular and cellular (screening) techniques to understand the molecular underpinnings of SMCHD1 expression in the muscle. Our study focusses on a variety of regulatory processes, including both transcriptional and post-transcriptional regulators of SMCHD1 expression and function. We combine these assays with genetic studies of SMCHD1 mutation carriers (FSHD2 patients) to better understand the function of SMCHD1.

Relevance
There is currently no therapy available for FSHD. This project explores the potential of SMCHD1-based therapy in FSHD.

Financiering: Prinses Beatrix Spierfonds; Spieren voor Spieren