Toxic protein linked to muscular dystrophy, rare facial malformation

NIEHS researchers and their colleagues have found that a toxic protein made by the body called DUX4 may be the cause of two very different rare genetic disorders. For patients who have facioscapulohumeral muscular dystrophy (FSHD) or who have a rare facial malformation called arhinia, this research discovery may eventually lead to therapies that can help people with these rare diseases.

Rare Disease Day is observed globally each year on the last day of February. The National Center for Advancing Translational Sciences (NCATS) and the NIH Clinical Center host Rare Disease Day at NIH. Learn more about the 2023 event here. (Image courtesy of EURORDIS)

Moving science forward

FSHD type 2 (FSHD2) is an inherited form of muscular dystrophy that causes progressive muscle weakness. Arhinia is an extremely rare yet severe disorder that prevents the development of an external nose and the olfactory bulbs and tracts. Both diseases are caused by mutations in the SMCHD1 gene. In patients with FSHD2, there is overproduction of DUX4, which kills the muscle cells, and this leads to the progressive weakening of the muscles.

“It has been known for some time that DUX4 damages the muscle in patients with FSHD2, but what we found is that it can actually also kill the precursors of the human nose,” said Natalie Shaw, M.D., head of the Pediatric Neuroendocrinology Group at the NIEHS and lead author of the new study in the journal Science Advances. NIEHS is part of National Institutes of Health (NIH).

One or the other but not both

Shaw’s team found that the combination of the mutated SMCHD1 gene and an environmental modifier, such as a virus, may trigger the DUX4 toxic protein. This may be what causes arhinia to occur. Using stem cells created from patients with the two diseases, the researchers conducted studies in cranial placode cells, the cells that lead to the development of the body’s sensory organs, such as the nose. As the placode cells started to form, they began to produce the DUX4 protein that caused cell death.

Natalie Shaw, M.D. — Shaw and colleagues have identified new information that will help scientists better understand how a gene mutation leads to two very different rare diseases. (Photo courtesy of Steve McCaw / NIEHS)

The researchers showed that DUX4 is responsible for cell death in placode cells as it is in muscle cells, but they still do not understand why the nose cells do not die in muscular dystrophy or why the muscle cells are not dying in arhinia.

“Now what we have to do is try to figure out the players acting downstream of DUX4, so we can block it from damaging the muscle cells or the nose precursors and hopefully find some new treatment options for patients suffering from these rare diseases,” said Shaw.

It takes a village

The NIEHS researchers have collaborated with researchers at the University of Iowa Carver College of Medicine, Iowa City, which is also the home of a Wellstone Muscular Dystrophy Specialized Research Center.

The Centers of Excellence program in muscular dystrophy research was established by NIH in 2003, in honor of the late Senator Paul D. Wellstone, Ph.D., of Minnesota. The six Wellstone Centers are funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI). The Iowa Wellstone Center is funded by NINDS.

Citation: Inoue K, Bostan H, Browne MR, Bevis OF, Bortner CD, Moore SA, Stence AA, Martin NP, Chen SH, Burkholder AB, Li JL, Shaw ND. 2023. DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose. Sci Adv 9(7):eabq7744.

(Robin Mackar is a writer and media relations coordinator in the NIEHS Office of Communications and Public Liaison.)