What is PCD Disease

When cilia no longer flicker

20.01.2011

Primary ciliary dyskinesia (PCD) is a severe chronic disease of the airways in which the function of the cilia, the cilia, is particularly severely impaired. A team of researchers from the Freiburg University Medical Center has now identified changes (mutations) in two genes that cause this disease.

Primary ciliary dyskinesia (PCD) is a serious congenital disease and affects one in 20,000 newborns in Germany. "Those affected suffer from chronic airway inflammation from an early age," explains Anita Becker-Heck, biologist at the Clinic for Neuropaediatrics and Muscle Diseases at the Freiburg University Medical Center. That means: constant bronchitis, constant sinusitis, constant runny nose - and not just in winter, but possibly for a lifetime.

For years, Becker-Heck has been researching together with colleagues from Prof. Dr. med. Heymut Omran at the Freiburg University Hospital investigated the genetic causes of this disease. In 2002 they had already identified a gene that is responsible for a variety of PCD. Now the Freiburg working group has been able to identify two more responsible genes. Since 1998, more than 1,000 patients have been examined in a study at the Clinic for Neuropaediatrics and Muscle Diseases (see Nature Genetics, online advance publication on December 5, 2010).

"In PCD, the function of the cilia, the so-called cilia, is particularly severely disturbed," explains Anita Becker-Heck. “The cilia in the lungs are crucial for the transport of mucus and bacteria. They clean the airways of germs. If the cilia no longer move properly or are completely immobile, chronic inflammation of the upper and lower airways can occur. ”Movable cilia are not only found in the lungs: in the embryo, they are crucial for the correct arrangement of the organs in the body. In around half of those affected, the internal organs are positioned the wrong way round (situs inversus). Some PCD patients also have a congenital heart defect.

Individual cilia are each made up of several hundred proteins. Of these, however, only a few are decisive for the mobility of these highly specialized organelles. If one of these proteins is missing, this leads to the functional disruption of the cilia. Depending on which protein is missing, dysfunctional cilia, for example, have defective beat patterns or are completely immobile.

It is true that different genetic defects that cause PCD have already been described. But for many of those affected, the genetic causes of their specific PCD disease are still in the dark. The Freiburg researchers have now been able to narrow this circle even further. “There are different methods of proving the presence of a PCD,” explains Anita Becker-Heck: “Using high-frequency video microscopy, one can directly demonstrate the mobility of ciliated cells from the nose. Under the electron microscope, we can examine the typical ultrastructure of a patient's cilia and recognize changes. Finally, immunofluorescence microscopy can show which proteins are actually missing in the cilia. "

Using the methods mentioned above, the Freiburg researchers were able to divide PCD sufferers into different groups in order to simplify the search for new genetic defects. "In our study with 750 PCD sufferers, a group of 31 patients was characterized by a very stiff ciliate and a lack of radial spokes", Anita Becker-Heck explains the research results. "In addition, proteins from the inner dynein arm (DNALI1) and the dynein-regulating complex (GAS11), which are crucial for normal ciliary movement, are missing in the cilia."
“We were able to identify two new genes that are defective in patients with missing radial spokes,” says Becker-Heck. The identification was made in cooperation with developmental biologists from the USA who work with zebrafish and mice, a research team from France who also researches PCD in humans and geneticists from Belgium who have examined dogs (Bobtails) with PCD. Like humans, fish and dogs have the same ultrastructural defect.
The genes CCDC39 and CCDC40 (coiled coil domain containing protein) are based on two proteins that occur in the cilia and are crucial for their correct ultrastructure.

With the help of DNA sequencing, mutations in these genes could be identified in the Freiburg patient group as well as in the zebrafish, the mice and the sick dogs. Over 50 percent of the patients examined with missing radial spokes carry mutations in CCDC40, and about 15 percent have mutations in the gene CCDC39. All patients with defects in one of the two genes as well as the sick dogs suffer from the typical chronic inflammation of the airways and more than half of the patients have a situs inversus.

According to the researchers, screening for mutations in these two genes could improve the diagnosis of PCD in the future. In addition, researching proteins could contribute to an understanding of cilia mobility.

Source: Freiburg University Medical Center