Pathogenic KIAA0586/TALPID3 variants are associated with defects in primary and motile cilia

Pathogenic KIAA0586/TALPID3 variants are associated with defects in primary and motile cilia

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 famil...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:iScience
Subjects:
Cell biology
Cellular physiology
Human Genetics
Integrative aspects of cell biology
Online Access:http://www.sciencedirect.com/science/article/pii/S2589004224028979
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Summary: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.
ISSN:2589-0042

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