MDA awarded a research grant totaling $260,000 over two years to Rossella Tupler, research assistant professor in the program of molecular medicine at the University of Massachusetts Medical School in Worcester. The funds will help support Tupler’s search for the molecular cause of facioscapulohumeral muscular dystrophy (FSHD).

FSHD has been associated with a reduction (eight or fewer) in the number of D4Z4 elements (alleles) and the subsequent expression (gene activity) of DUX4, Tupler explains. “However, studies of families in Italy, Brazil and the United States suggest that D4Z4 reduction and DUX4 expression are not sufficient to cause disease.”

In Italian families, a study of 253 unrelated people with FSHD revealed that 204 (80.6 percent) carry D4Z4 alleles with 1-8 units, 19 (7.5 percent) have D4Z4 alleles with 9-10 repeats, and 30 (11.8 percent) carry D4Z4 alleles with 11 repeats or more.

In the United States, family members with identical D4Z4 repeat lengths included members who did not have the disease and members with classical FSHD; not all had DUX4 activity. 

“Collectively, these results indicate that those DNA anomalies are not sufficient to cause FSHD and additional factors are necessary to disease development,” Tupler says.

With colleagues, Tupler is working to identify genetic elements that can cause FSHD disease onset. The team is using a technique called whole-genome sequencing to study the DNA of 12 families from Italy, Brazil and the United States in which D4Z4 reduction does not correlate with the presence of disease.

“A profound rethinking of the genetic disease mechanism and modes of inheritance of FSHD is now required,” Tupler says, “and entirely new models and approaches are needed.”

Funding for this MDA grant began Aug. 1, 2012.