You probably haven't heard of primary ciliary dyskinesia. It's a genetic disorder that affects only one in 20,000 babies, mostly by causing chronic respiratory problems. What makes it even trickier is that, because it's so rare, and because respiratory problems are caused by a wide range of things, it's difficult to pinpoint, let alone cure.
But now a team of researchers at Washington University Medical School believe they've found one of the genetic errors that causes ciliary dyskenesia.
Ciliary dyskinesia affects the cilia, microscopic hairs that line the respiratory system, from the ears and nose to the lungs. Normally, the cilia beat constantly, about ten times per second, to clear out pollutants and bacteria. In patients with ciliary dyskinesia, though, the cilia work badly or not at all, which leads to the constant colds and snuffling and ear and sinus infections.
The disease can cause other, prenatal problems, too: While an embryo is still developing, the cilia behave like small antennae, picking up signals about which organs should go where. If the cilia aren't working properly, organs can end up in the wrong place.
To make matters even more confusing, doctors can't diagnose a case of ciliary dyskinesia just by looking at cilia under a microscope. Some patients have weird-looking cilia, but in other patients, the cilia look completely normal.
It would be so much easier if you could just do a genetic test to figure out if you've got ciliary dyskinesia or not.
Enter gene HEATR2.
Dr. Thomas Ferkol and his colleague Dr. Amjad Horani, both of whom specialize in pediatric pulmonology, sequenced the genes of two people with ciliary dyskinesia and compared them to the genes of their parents, who don't have the disease. (Everyone in the study is related; they belong to a large Amish clan spread across Missouri, Arkansas and Wisconsin, and the disease runs in the family: nine members have it.)
The problem, it appeared, came from a mutation in the gene known as HEATR2, which makes a protein that makes the cilia's "motors" run.
"In these patients," Ferkol explains, "the cilia motors are not assembled properly and they just sputter."
The doctors confirmed their hypothesis by doing some lab experiments in which they "silenced" HEATR2 in normal human cells and also in green algae. (The lab team included not just other pulmonologists, but an engineer who specializes in the mechanics of beating cilia and a geneticist who studies green algae.) The motors in the cilia in those cells shut down, too.
The discovery of HEATR2's involvement with ciliary dyskinesia brings the number of genes associated with the disease up to fifteen. That still only accounts for less than half the cases of ciliary dyskinesia, but it's progress. Ferkol also hopes that by finding out more about ciliary dyskinesia, he'll also be able to uncover a few more clues about what causes other respiratory problems.
"Many young children without primary ciliary dyskinesia experience chronic or repeated sinus or ear infections," he says. "It is possible that a more subtle error in one of more genes linked to this rare disorder may be at the root of these common conditions.
"Ultimately," he continues, "we want to identify all the mutations responsible for primary ciliary dyskinesia. In our dreams, we hope that one day we can correct ciliary defects that lead to respiratory disease. But in the short term, a more complete understanding of the genetics of primary ciliary dyskinesia will be a huge step forward toward improving diagnosis and allow us to better connect particular mutations with specific symptoms."