Identification of DNA Region Necessary for FSHD

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An international collaboration of scientists, including researchers supported by funding from the Friends of FSH Research, has made an exciting breakthrough that brings hopes of a cure closer to reality. This important research, published in one of the world's most prestigious science journals, Science, solves part of a mystery that has plagued FSHD research.

For more than twenty years, scientists have known that a specific region on chromosome 4 was tied to 97% of cases of FSHD (FSHD Type I), but have been stymied in their efforts to narrow in on the specific change or changes which cause the disease. They knew that all FSHD Type I patients, unlike healthy humans, had fewer than 10 copies of a particular repeated genetic sequence in that chromosome called D4Z4, but no one could explain how this shortening could cause FSHD. The recent breakthrough provided part of the answer, with the remaining portion to be provided by a soon-to-be published paper submitted by the same team of international researchers.

Although this international collaboration of FSHD scientists have been working together for many years, only in the past couple years have they been investigating the DUX4 gene, which has otherwise been largely ignored in the scientific community. However, scientists found that having fewer than 10 copies of D4Z4 changes the structure of chromosome 4 in a way that allows the body to transcribe, or express, the DUX4 gene in FSHD Type I skeletal muscle cells as DUX4 RNA. However, this alone does not cause the disease. The researchers also discovered that the DUX4 gene is not normally translated to protein because the RNA expression of the gene breaks down rapidly due to the fact that the mRNA (messenger RNA) is missing a strong polyadenylation signal required to stabilize it. In FSHD patients, however, a unique genetic sequence causes mRNA to be stabilized, and hence translated to DUX4 protein, known to be toxic to skeletal muscle. Only the combination of having both fewer copies of D4Z4 and the unique sequence results in FSHD Type I. Solving this complicated disease pathway was a tremendous scientific feat that is expected to greatly benefit FSHD research.

The fight is not yet over. Now that the cause of FSHD is clearer, researchers still need your support to apply that knowledge to determine what fatal consequences this gene product is causing to FSHD patient’s muscles, to develop treatments to stop this process, and finally to find a cure. But having made such a difference in helping achieve this breakthrough, we can be confident that the end is now in sight.

See Science article

A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

Richard J. L. F. Lemmers,1 Patrick J. van der Vliet,1 Rinse Klooster,1 Sabrina Sacconi,2 Pilar Camaño,3,4 Johannes G. Dauwerse,1 Lauren Snider,5 Kirsten R. Straasheijm,1 Gert Jan van Ommen,1 George W. Padberg,6 Daniel G. Miller,7 Stephen J. Tapscott,5 Rabi Tawil,8 Rune R. Frants,1 Silvère M. van der Maarel1*

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35 but this contraction is pathogenic only in certainpermissivechromosomal backgrounds. Here we show that FSHD patients carry specific single nucleotide polymorphisms (SNPs) in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.

1Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
2Centre de reference pour les maladies Neuromusculaires and CNRS UMR6543, Nice University, 06202 Nice, France.
3Department of Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, 20014 San Sebastián, Spain.
4CIBERNED, Instituto de Salud Carlos III, 28029 Madrid, Spain.
5Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
6Department of Neurology, Radboud University Medical Center Nijmegen, 6500 HC Nijmegen, Netherlands.
7Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
8Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.

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