CFAP300 mutation causing primary ciliary dyskinesia in Finland

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.

HYDINvariants cause primary ciliary dyskinesia in the Finnish population

“…Our study has shown that HYDIN variants explain 22% of the analysed cases (4/16) in the Finnish patient cohort. Other recurrent PCD-causing variants were previously reported in CFAP300 (17%, three families) and DNAH11 (11%, two families) (Schultz, Elenius et al 2020, Schultz, Elenius et al 2022). There is still work to be done to establish a more complete gene panel for genetic diagnostics in Finland, but several Finnish population enriched variants have been identified thus far and this information can be used for improving clinical diagnostics for PCD.…”

“…In Finland genetic mutations in PCD patients have previously been identified only in the DNAH11 and CFAP300 genes (Schultz, Elenius et al 2020, Schultz, Elenius et al 2022). The HYDIN variants identified in this study contribute to the understanding of the genetic background of PCD in Finland and enable development of genetics diagnostics within the Finnish population.…”

“…Nasal epithelial cells were suspended in a DMEM medium and evaluated under a differential-interference microscope (Zeiss, Oberkochen, Germany) at x1000 magnification and cilia beat was recorded with a digital high-speed video (DHSV) camera (Hamamatsu Orca Flash 4.0, Hamamatsu Japan) with a frame rate of 256 Hz. The detailed protocol for HSVA can be found in Schultz et al 2022. DHSV video sequences were played back frame by frame to determine the cilia beat frequency (CBF) by calculating the mean of all recorded cilia beat cycles.…”

Primary Ciliary Dyskinesia and Type 1 Diabetes: True Association or Circumstantial?

“…A previous study reported that genetic, immunologic, and environmental factors may increase the risk for type 1 diabetes mellitus (T1DM) [ 7 , 8 ]. The role of PCD in the development of T1DM has yet to be determined.…”