PHG Foundation | New study points the way to muscular dystrophy therapies

New study points the way to muscular dystrophy therapies
20 August 2010 | By Simon Leese | Research article

A study published yesterday in Science [Lemmers et al. (2010) Science 19 Aug doi:10.1126/science.1189044] has uncovered the mystery cause of a form of muscular dystrophy pointing the way towards possible therapies.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the more common forms of muscular dystrophy - affecting around 1 in 20,000 people - and is characterised by progressive weakening of muscles in the face, shoulders and upper arms. Its mechanism was unknown and thus no effective therapies exist.

All that was known previously was that FSHD was associated with a shortened repeating DNA sequence on chromosome 4, but that this alone was not enough to cause the disease. No direct gene association had been found. The same repeats are present on chromosome 10, but only those on chromosome 4 are associated with the disease.

Within each repeating unit is a gene called DUX4 that had been thought to be an ancient ‘dead’ gene that was no longer expressed. This study found that the gene was in fact always transcribed, but that the RNA transcripts were unstable and immediately degraded because they lacked a poly(A) tail – a short sequence that marks an RNA transcript for expression.

This study found that the DNA adjacent to the repeat region on chromosome 4 contained the sequence ATTAAA, and that all the families with FSHD that they examined had specific SNPs causing this sequence to be appended to their DUX4 transcripts. This sequence was not found on chromosome 10. It was further found that DUX4 RNA was present in the muscle cells of people with FSHD, but not in those without the condition. Earlier studies had already shown that DUX4 can trigger muscle cell death.

Comment: This study suggests a plausible genetic model for FSHD whereby specific polymorphisms create stable DUX4 transcripts which in turn become proteins that cause muscle damage. This points the way towards clear therapeutic targets and will undoubtedly lead to studies into methods by which the DUX4 gene or its proteins can be deactivated. Some caution should be exercised however in concluding that the mechanism of FSHD has been fully revealed, since the SNPs that the researchers identified were in a small sample size of just four families
PHG Foundation | New study points the way to muscular dystrophy therapies