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A unifying genetic model for facioscapulohumeral muscular dystrophy
Richard J L F Lemmers1, Patrick J van der Vliet, Rinse Klooster
1Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
Science (New York, N.Y.)
|August 21, 2010
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is linked to specific genetic variations near D4Z4 repeats. These variations stabilize the DUX4 gene transcript, causing a toxic gain of function that leads to muscle wasting.
Area of Science:
- Genetics
- Molecular Biology
- Neuromuscular Disorders
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent adult muscular dystrophy.
- It involves progressive upper body muscle wasting.
- FSHD pathogenesis is linked to D4Z4 macrosatellite repeat contraction on chromosome 4q35, but only in specific permissive genetic contexts.
Purpose of the Study:
- To investigate the specific genetic factors contributing to FSHD in permissive chromosomal backgrounds.
- To elucidate the molecular mechanism underlying FSHD, focusing on the DUX4 gene.
Main Methods:
- Analysis of single-nucleotide polymorphisms (SNPs) in the chromosomal region distal to D4Z4 repeats in FSHD patients.
- Transfection studies to assess DUX4 transcript polyadenylation and stability.
Main Results:
- FSHD patients with permissive backgrounds possess specific SNPs distal to the D4Z4 repeat.
- This configuration creates a polyadenylation signal for DUX4 transcripts.
- DUX4 transcripts are more efficiently polyadenylated and stabilized in permissive genetic backgrounds.
Conclusions:
- FSHD may result from a toxic gain of function.
- This gain of function is attributed to a stabilized distal DUX4 transcript.
- Specific genetic variations create a pathogenic DUX4 transcript, driving FSHD development.
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