Molecular characterization of defects of the nexin-dynein regulatory complex causing Primary Ciliary Dyskinesia (PCD)
Final Report Abstract
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by insufficient mucociliary clearance, leading to chronic airway infections. Cilia are tiny projections responsible for cell motility and involved in various physiological processes such as breathing, organ development, and reproduction. The structure of motile cilia, which exhibit a 9+2 microtubule arrangement, is crucial for their function, particularly for airway clearance. A key component of cilia is the Nexin-Dynein Regulatory Complex (N-DRC), which regulates ciliary movement. Defects in genes encoding components of this complex, such as CCDC39 and CCDC40, result in PCD and other conditions like male infertility due to ciliary defects in sperm. Our Project explored the genetic basis and clinical manifestations of PCD, particularly concerning N-DRC components. The project's goals included: 4. Identifying new genes linked to axonemal disorganization and inner dynein arm defects in PCD. 5. Validating new candidate genes. 6. Investigating genotype-phenotype correlations. We discovered various novel pathological genetic variants, including novel variants in CCDC39 and CCDC40, which lead to impaired ciliary movement and infertility. Particularly interesting was the finding that men with these pathological genetic variants experienced infertility due to sperm flagella defects, alongside respiratory symptoms. These men displayed typical features of MMAF (Multiple Morphological Abnormalities of the Flagella), such as irregular flagella and reduced sperm count. Essential for this finding was the detection of CCDC39 and CCDC40 in sperm flagella using immunofluorescence microscopy, offering new diagnostic approaches to identify ciliary defects in male infertility. We also found that pathogenic variants in other N-DRC components, including mutations in two candidate genes, impair ciliary function both in the respiratory system and the male reproductive system. This project contributed significantly to the understanding of PCD, particularly in terms of genetics and clinical manifestations, and layed the groundwork for new diagnostic methods and therapies, improving the quality of life in affected individuals.
Publications
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Limitations of Nasal Nitric Oxide Measurement for Diagnosis of Primary Ciliary Dyskinesia with Normal Ultrastructure. Annals of the American Thoracic Society, 19(8), 1275-1284.
Raidt, Johanna; Krenz, Henrike; Tebbe, Johannes; Große-Onnebrink, Jörg; Olbrich, Heike; Loges, Niki Tomas; Biebach, Luisa; Schmalstieg, Christian; Keßler, Christina; Wallmeier, Julia; Dworniczak, Bernd; Pennekamp, Petra; Dugas, Martin; Werner, Claudius & Omran, Heymut
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Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility. Frontiers in Genetics, 14.
Aprea, I.; Wilken, A.; Krallmann, C.; Nöthe-Menchen, T.; Olbrich, H.; Loges, N. T.; Dougherty, G. W.; Bracht, D.; Brenker, C.; Kliesch, S.; Strünker, T.; Tüttelmann, F.; Raidt, J. & Omran, H.
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Primary ciliary dyskinesia. La Presse Médicale, 52(3), 104171.
Raidt, Johanna; Loges, Niki Tomas; Olbrich, Heike; Wallmeier, Julia; Pennekamp, Petra & Omran, Heymut
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Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations. European Respiratory Journal, 64(2), 2301769.
Raidt, Johanna; Riepenhausen, Sarah; Pennekamp, Petra; Olbrich, Heike; Amirav, Israel; Athanazio, Rodrigo A.; Aviram, Micha; Balinotti, Juan E.; Bar-On, Ophir; Bode, Sebastian F.N.; Boon, Mieke; Borrelli, Melissa; Carr, Siobhan B.; Crowley, Suzanne; Dehlink, Eleonora; Diepenhorst, Sandra; Durdik, Peter; Dworniczak, Bernd; Emiralioğlu, Nagehan ... & Omran, Heymut
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Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. Cells, 13(14), 1200.
Wilken, Alina; Höben, Inga Marlena; Wolter, Alexander; Loges, Niki Tomas; Olbrich, Heike; Aprea, Isabella; Dworniczak, Bernd; Raidt, Johanna & Omran, Heymut
