Scientists ID Molecular Consequences of FSHD Mutation

MDA grantee Davide Gabellini was on a research team at the University of Massachusetts Medical School in Worcester that has found a new piece of the puzzle of facioscapulohumeral muscular dystrophy (FSHD) by identifying specific consequences of a previously known mutation that removes a section of DNA. They also developed the first reliable mouse model of FSHD.

In 2002, Gabellini and colleagues found that a missing section of DNA on chromosome 4, called D4Z4, normally acts as a suppressor of other genes near the D4Z4 region. (See “MDA Scientists Find New Disease Mechanism Causes Common Dystrophy.”)

Since then, a search for genes in the region that, if activated instead of suppressed, might cause muscle degeneration, has turned up several candidates, but nothing definitive.

Now, scientists from the University of Massachusetts and from Milan and Pavia, Italy, who published their findings online in Nature, have determined that a gene known as FRG1 (for FSHD region gene 1) is a major suspect in causing FSHD.

When they analyzed genetically altered mice that produced low, medium or high levels of the FRG1 protein, they found that the higher the FRG1 levels were, the worse the MD symptoms were in the mouse. Mice with elevated FRG1 levels showed spinal curvatures, muscle wasting (atrophy), increased connective tissue in the muscles, and reduced exercise tolerance, along with muscles that appeared dystrophic under the microscope.

The muscles most affected were somewhat analagous to those affected in human patients with FSHD, although differences in mouse and human anatomy in the face and upper body make direct comparisons impossible.

Further experiments showed that FRG1 doesn’t produce its adverse effects directly, but rather indirectly, through at least two other proteins: TNNT3, which normally regulates muscle contractility, and MTMR1, which can regulate muscle atrophy.

The researchers say they think FRG1 is one of many genes that affect RNA splicing, a process that determines the final composition of a protein. They say the effects of high levels of FRG1 could range far beyond TNNT3 and MTMR1, possibly affecting hundreds or even thousand of other genes. “It is likely that the cumulative effect of decreased levels of many normal protein [forms] and increased levels of many aberrant protein [forms] is responsible for disease,” they say.

Gabellini said, however, that suppressing or blocking FRG1 might be all that’s needed to remedy the situation, suggesting a rational approach to therapy development on a molecular level. He also noted that FRG1 mice could be used as a preclinical model to test potential therapies for FSHD.