Pathogenic KIAA0586/TALPID3 variants are associated with defects in primary and motile cilia
Jacqueline E. Taudien,
Diana Bracht,
Heike Olbrich,
Sebastian Swirski,
Fulvio D’Abrusco,
Bert Van der Zwaag,
Maike Möller,
Thomas Lücke,
Norbert Teig,
Ulrika Lindberg,
Kai Wohlgemuth,
Julia Wallmeier,
Anja Blanque,
Christos Gatsogiannis,
Sebastian George,
Christoph Jüschke,
Marta Owczarek-Lipska,
Dorothee Veer,
Hester Y. Kroes,
Enza Maria Valente,
G. Christoph Korenke,
Heymut Omran,
John Neidhardt
Affiliations
Jacqueline E. Taudien
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany
Diana Bracht
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
Heike Olbrich
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
Sebastian Swirski
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany
Fulvio D’Abrusco
Neurogenetics Research Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy
Bert Van der Zwaag
Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center of Utrecht, 3584 CX Utrecht, the Netherlands
Maike Möller
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany
Thomas Lücke
Department of Neuropaediatrics and Social Paediatrics, University Children’s Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
Norbert Teig
Department of Neonatalogy, University Children’s Hospital, Ruhr-University Bochum, 44791 Bochum, Germany
Ulrika Lindberg
Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund, Sweden
Kai Wohlgemuth
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
Julia Wallmeier
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
Anja Blanque
Institute for Medical Physics and Biophysics and Center for Soft Nanoscience (SoN), Westfälische Wilhelms University Münster, 48149 Münster, Germany
Christos Gatsogiannis
Institute for Medical Physics and Biophysics and Center for Soft Nanoscience (SoN), Westfälische Wilhelms University Münster, 48149 Münster, Germany
Sebastian George
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
Christoph Jüschke
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany
Marta Owczarek-Lipska
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany; Research Center Neurosensory Science, University of Oldenburg, 26129 Oldenburg, Germany
Dorothee Veer
Social-pediatric Outpatient and Therapy Center, Hospital Ludmillenstift, 49716 Meppen, Germany
Hester Y. Kroes
Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center of Utrecht, 3584 CX Utrecht, the Netherlands
Enza Maria Valente
Neurogenetics Research Centre, IRCCS Mondino Foundation, 27100 Pavia, Italy; Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
G. Christoph Korenke
University Children’s Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, 26133 Oldenburg, Germany
Heymut Omran
Department of General Paediatrics, University Hospital Muenster, 48149 Muenster, Germany
John Neidhardt
Human Genetics, School of Medicine and Health Sciences, Carl von Ossietzky Universität Oldenburg, 26129 Oldenburg, Germany; Research Center Neurosensory Science, University of Oldenburg, 26129 Oldenburg, Germany; Corresponding author
Summary: Pathogenic variants in KIAA0586/TALPID3 are associated with the ciliopathy Joubert syndrome (JS). We report individuals with KIAA0586/TALPID3 variants affected by primary and motile cilia defects leading to JS and chronic destructive airway disease. DNA variants were detected in three families by sequencing. In two unrelated families, a deep-intronic variant (KIAA0586/TALPID3:c.3990 + 3186G>A) activated a cryptic exon. We performed histological and functional analyses in native and air-liquid interface (ALI) cultured respiratory cells. Primary cilia lengths were measured in patient-derived fibroblasts. Our data associate KIAA0586/TALPID3 variants with a syndrome combining JS and chronic destructive airway disease, reduced number of motile cilia, disorganized basal body location, and ciliary clearance malfunction. Additionally, patient-derived cell lines showed primary cilia defects. Disease causing KIAA0586/TALPID3 variants, including a deep-intronic sequence variant, were associated with primary and motile cilia defects in JS patients. The combination of JS and respiratory symptoms should be considered indicative for KIAA0586/TALPID3 sequence alterations.
