Genetic mutation associated with a form of muscular dystrophy can also block nose development

2023

Challenge

Congenital arrhinia is an extremely rare birth defect that causes the complete absence of a nose. Researchers led by IRP Lasker Clinical Research Scholar Natalie Shaw, M.D., have linked the condition to a mutation in the gene SMCHD1, which controls how other genes function. This discovery was surprising because mutations in SMCHD1 were already known to cause a completely different disorder, a rare form of muscular dystrophy called FSHD2 that particularly affects facial muscles. However, it remained unclear why changes in the SMCHD1 gene cause arrhinia.

Advance

Dr. Shaw’s group identified the mechanism through which SMCHD1 mutations lead to arrhinia. Using human embryonic stem cells that lacked the SMCHD1 gene and induced pluripotent stem cells (iPSCs) grown from arrhinia patients’ cells, the researchers showed that when the primitive cells that give rise to sensory organs like the nose start to mature into nerve cells, the lack of a functional SMCHD1 gene causes them to die. Interestingly, a toxin produced in embryonic tissue called DUX4, the same chemical that causes cell death in FSHD2, was responsible for the death of immature sensory cells in arrhinia. The researchers also showed that infecting those early sensory cells with a form of the herpes virus triggered production of the DUX4 toxin, suggesting that viruses may be an environmental cause of arrhinia.

Impact

This is the first report of a birth defect caused by a toxic protein made by the body itself. In addition, the study provides an excellent example of how studying a rare disease like arrhinia can shed light on more common conditions like FSHD2. For instance, the findings could spur future research exploring what controls DUX4 production and what causes DUX4 to be toxic to immature sensory cells in arrhinia patients, which may improve our understanding of why DUX4 is toxic to muscle cells in patients with FSHD2 and, potentially, lead to new treatments.

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