FHCRC & UW Researchers Participate in Muscular Dystrophy Gene Discovery

Seattle/LocalHealthGuide has a story on the intercontinental team who have discovered the genetic link to a form of muscular dystrophy. Their paper, published in Science, details how expression of the DUX4 homeobox gene by an otherwise harmless stretch of “junk DNA” results in facioscapulohumeral muscular dystrophy (FSHD).

They’re hypothesizing that the DUX4 protein is at some level toxic to muscle cell development, which results in FSHD’s “weakness and wasting” of muscles in the face, shoulders, and upper arms–which can later reach the abdomen and hips. Eventually, it could be possible to medically disrupt the protein-encoding process–but for now identifying the protein in a lab’s controlled conditions and in the body are two very different things.

It’s now possible, given this discovery, to determine via DNA testing if someone has FSHD before symptoms have begun to display. (Even pre-natally.)

Researchers from the Fred Hutchinson Cancer Research Center, the University of Washington (Daniel Miller), and the University of Rochester Medical Center collaborated with scientists in the Netherlands and Spain. Dr. Stephen Tapscott, from the Hutch’s Division of Human Biology, was a co-author.

I spoke with Lauren Snider, from the Human Biology Division, about their lab’s role. “Most of the work was done by the group in Netherlands, at Leiden University,” she explained.

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“We provided the technical refinements that allowed us to understand what transcripts are expressed.” As you remember from biology, “Transcription is the first step leading to gene expression.” (Not all of their research made it into the paper–some played more of a supporting role in delineating genetic possibilities, but that’s science. There’s a lot of ruling in and ruling out to do.)

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Chromosome 4 has what’s called a macrosatellite repeat array (D4Z4), similar in layout to one on chromosome 10. Counterintuitively, the repeated sequences could continue 100 times with no problems. It was only when the sequences repeated ten times or less on chromosome 4 that FSHD resulted. (A shortened set of sequences on chromosome 10 had no ill effects.)

Researchers discovered that near the end of the D4Z4 sequence on chromosome 4 was a polyadenylation site, which, it turns out, is what gets the DUX4 protein expression party started. If the D4Z4 sequence goes on too long, the polyadenylation signal doesn’t “turn on” the protein-making process.

“The use of the predicted poly(A) signal was verified by 3′RACE,” reads the paper (that’s a Hutch contribution). Progress!