Multi-National Research - Making Strides for FSHD Research

Two genetic changes needed to cause FSHD

Facioscapulohumeral muscular dystrophy (FSHD) requires the presence of not one but two genetic changes, both on chromosome 4, MDA-supported scientists have found.
MDA grantee Silvère van der Maarel at Leiden (Netherlands) University Medical Center coordinated the multinational study team, which announced its findings online Aug. 19, 2010, in the journal Science.

Two genetic changes — a contracted segment of DNA on chromosome 4, and a "permissive" signal near it on the same chromosome — are necessary to complete the FSHD puzzle.

The investigators found that two genetic requirements, located near each other on the tip of chromosome 4, must be combined for FSHD symptoms to appear. One requirement is a deletion of some of the DNA in a region of chromosome 4 called D4Z4. Its contribution to FSHD has been recognized for many years. The second requirement, newly recognized, is a particular variant of DNA further toward the tip of chromosome 4 than the D4Z4 region.

The variant contains a “polyadenylation” signal, which stabilizes otherwise fragile genetic instructions called RNA transcripts, after they’re synthesized from DNA (genes).

The presence of a polyadenylation signal makes it more likely that genetic instructions will stick around long enough to be translated into proteins, the final product of DNA and RNA instructions. In this case, the signal appears to make it possible for one or more potentially toxic proteins to be produced.

More than 300 people with FSHD and more than 2,000 people without the disease were studied. All the people with FSHD had a contracted D4Z4 region on chromosome 4 and at least one of three “permissive” DNA sequences further out toward the tip of the same chromosome.

Among the more than 2,000 people without any FSHD symptoms that the investigators studied, some had contracted D4Z4 regions on chromosome 4. However, they all had “nonpermissive” signals further out on the chromosome.
Without a “permissive” polyadenylation signal, the researchers believe, genetic instructions (RNA) from the D4Z4 region don’t last long enough to cause muscle-cell damage.

The new findings will make it easier to diagnose FSHD in someone with symptoms and predict who will develop the disease among those without symptoms.
Once the identities of the toxic proteins or RNA instructions are established, therapeutic strategies to block them could potentially be developed.

(Part of the multi-national team responsible for these recent findings include Friends of FSH Research supported Seattle researchers - Thanks to everyone for your donations that made this work possible)