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Am J Respir Cell Mol Biol. 2019 Sep 23. doi: 10.1165/rcmb.2019-0086OC. [Epub ahead of print]

SPEF2- and HYDIN-mutant Cilia Lack the Central Pair Associated Protein SPEF2 Aiding PCD Diagnostics.

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University Children's Hospital Muenster, Department of General Pediatrics, Muenster, Germany.
University of Alberta, Pediatrics, Edmonton, Canada.
Dana-Dwek Children's Hospital, 108403, Tel Aviv, Israel.
1Danish PCD & chILD Centre, CF Centre Copenhagen, Pediatric Pulmonary Service Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Denmark, Coppenhagen, Denmark.
Copenhagen University Hospital, Pediatrics and Adolescent Medicine, Copenhagen, Denmark.
Danish PCD Centre, Pediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark , Copenhagen Ø, Denmark.
University Medicine Essen Ruhrlandklinik, 530897, Essen, Nordrhein-Westfalen, Germany.
University Children's Hospital Muenster, Department of General Pediatrics, Muenster, Germany;


Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal NO measurement, analysis of ciliary beating, transmission electron microscopy (TEM) and/or genetic testing. In most genetic PCD variants laterality defects can occur. However, PCD individuals with central pair (CP) defects are difficult to diagnose and require alternative strategies because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2 that is almost identical in intron-exon structure. We have previously shown that several PCD types can be diagnosed with immunofluorescence (IF) microscopy analyses. In PCD individuals with CP defects, we demonstrate by IF that the CP-associated protein SPEF2 is absent in HYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells of 189 individuals suspected with PCD and situs solitus. 41 of 189 individuals showed undetectable SPEF2 and were subject to genetic analysis, revealing one novel loss-of-function mutation in SPEF2, three reported and 13 novel HYDIN mutations among 15 individuals. The remaining 25 individuals are good candidates for new yet uncharacterized PCD variants affecting the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previsously been identified to cause PCD. We identified mutation of SPEF2 causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.


<italic>situs solitus</italic>; Cilia; central pair complex; immunofluorescence microscopy analysis; sensitivity and specificity


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