Genetic lung disease’s molecular roots identified

Respiratory infections peak during the winter months, and most people recover within a few weeks. But for those with a rare genetic lung disease, the sniffling, coughing and congestion never end. The tiny hairlike structures called cilia that normally sweep mucus through the airways don’t work properly in people with what’s known as primary ciliary dyskinesia. When the cilia don’t brush microbes away, it is hard to clear an infection and easy to get another one.

Most people with this disease carry mutations in one of the genes that build the proteins that form molecular motors inside cilia. A single misshapen piece of protein can make the whole machine grind to a halt. But a few people have errors in proteins that are not part of the motor. Until now, no one understood why their cilia don’t beat.

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1986 University alumnus Michael Yarbrough, manager of community outreach and player involvement with the St. Louis Rams, chats with students (from left) Amy Katz, Kate Gerber and Erica Sampson during a recent networking reception sponsored by The Career Center. The reception allowed current students to meet with alumni and discuss job searching and career opportunities.

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The HEATR2 protein (red) is located in the body of airway cells lining the trachea, not in the cilia (green) or the nuclei (blue). Finding HEATR2 outside of the cilia was Horani and Brody’s first clue that the protein did not form part of the cilia’s motor. Later, they discovered that HEATR2 formed the scaffold on which the motor was built. (Image: Amjad Horani)

With the help of David Piston, PhD, the Edward Mallinckrodt Jr. Professor and head of the Department of Cell Biology and Physiology, and staff scientist Alessandro Ustione, PhD, the researchers showed that the three proteins form a scaffold on which the molecular motor later is to be built.

Horani swabbed the noses of some of his patients and grew ciliated cells from them. He found that the scaffold is constructed incorrectly in cells with mutations in any of the three early genes. The proteins that comprise the motor arrive at the faulty scaffolding, but rather than passing through an efficient assembly line and forming a motor, they collect haphazardly into a heap.

“Piling together misfolded proteins turns out to be the way that the body tries to get rid of abnormal proteins,” Horani said. “Now that we know what is wrong, we want to find out, ‘How can we make this work?’ We’re starting to study whether we can prevent the protein heaps from forming and somehow rescue the parts of the motors. If we can get just a few of these proteins to assemble, we may be able to improve quality of life for people with this disease.”

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