DUX4 and D4Z4 RNA and protein production as candidates for FSHD

Investigator: Stephen Tapscott MD PhD

Category: Research - Basic

Official Title: Identifying potential mechanisms for FSHD

Dr. Tapscott aims to use this grant to identify the potential mechanisms that cause FSHD. Dr Tapscott will identify the molecular changes that result from the FSHD mutation. This will allow him/her to find out the molecular mechanisms that might cause FSHD and then test which mechanism might the most important for the development of therapies.

Contents

• What are the researchers aiming to do?
• How will the outcomes of the research benefit patients?
• Background information

What are the researchers aiming to do?

Deletion of a subset of the D4Z4 repeats on chromosome 4qA results in a decrease of repressive chromatin markings and all individuals with FSH muscular dystrophy have at least one full, or one partial, D4Z4 repeat sequence remaining intact on 4qA. This has led to the hypothesis that a transcript from this region, or an adjacent region, is expressed on the deleted allele due to loss of repressive chromatin. Despite the attractiveness of this hypothesis, investigators have not shown elevation of the full-length DUX4-encoding transcripts in FSHD, or consistently shown elevation of other regional transcripts, such as FRG2 or ANT1. Our preliminary studies show that multiple small RNA transcripts arise from the 4qA D4Z4, whereas the full-length DUX4 encoding transcript is not detected. We will test the hypothesis that these RNAs or their encoded peptides contribute to the pathophysiology of FSHD independently of the full-length DUX4. The specific aims of the proposal will: (Aim 1) Determine whether alternative peptides or ORFs contribute to disease pathology in FSHD; (Aim 2) determine whether an RNA mediated mechanism might contribute to FSHD pathology; (Aim 3) develop collaborations with other FSHD researchers to extend these studies to relevant mouse and human models and to develop therapeutic interventions.

How will the outcomes of the research benefit patients?

We have identified new molecular mechanisms for the pathophysiology of FSHD and the significance of this proposal is that the validation of a specific mechanism for FSHD pathophysiology is the first necessary step for the development of therapeutic interventions.

Background information

Deletion of a subset of the D4Z4 repeats on chromosome 4qA results in a decrease of repressive chromatin markings and all individuals with FSH muscular dystrophy have at least one full, or one partial, D4Z4 repeat sequence remaining intact on 4qA. This has led to the hypothesis that a transcript from this region, or an adjacent region, is expressed on the deleted allele due to loss of repressive chromatin. Despite the attractiveness of this hypothesis, investigators have not shown elevation of the full-length DUX4-encoding transcripts in FSHD, or consistently shown elevation of other regional transcripts, such as FRG2 or ANT1. Our preliminary studies show that multiple small RNA transcripts arise from the 4qA D4Z4, whereas the full-length DUX4 encoding transcript is not detected. We will test the hypothesis that these RNAs or their encoded peptides contribute to the pathophysiology of FSHD independently of the full-length DUX4.

Related Material

See resulting Developmental Cell publication DUX4 activates germline genes, retroelements and immune-mediators: Implications for facioscapulohumeral dystrophy.