posted on 2024-09-10, 09:35authored byAshleigh Howes, Clare Rogerson, Nikolai Belyaev, Tina Karagyozova, Radu Rapiteanu, Ricardo Fradique, Nicola Pellicciotta, David Mayhew, Catherine Hurd, Stefania Crotta, Tanya Singh, Kevin Dingwell, Anniek Myatt, Navot Arad, Hikmatyar Hasan, Hielke Bijlsma, Aliza Panjwani, Vinaya Vijayan, George Young, Angela Bridges, Sebastien Petit-Frere, Joanna Betts, Chris Larminie, James C Smith, Edith M Hessel, David Michalovich, Louise Walport, Pietro Cicuta, Andrew J Powell, Soren Beinke, Andreas Wack
SNPs in the FAM13A locus are amongst the most commonly reported risk alleles associated with chronic obstructive pulmonary disease (COPD) and other respiratory diseases, however the physiological role of FAM13A is unclear. In humans, two major protein isoforms are expressed at the FAM13A locus: 'long' and 'short', but their functions remain unknown, partly due to a lack of isoform conservation in mice. We performed in-depth characterisation of organotypic primary human airway epithelial cell subsets and show that multiciliated cells predominantly express the FAM13A long isoform containing a putative N-terminal Rho GTPase activating protein (RhoGAP) domain. Using purified proteins, we directly demonstrate RhoGAP activity of this domain. In Xenopus laevis, which conserve the long isoform, Fam13a-deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long isoform deficiency did not affect multiciliogenesis but reduced cilia co-ordination in mucociliary transport assays. This is the first demonstration that FAM13A isoforms are differentially expressed within the airway epithelium, with implications for the assessment and interpretation of SNP effects on FAM13A expression levels. We also show that the long FAM13A isoform co-ordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Funding
Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics)
Crick (Grant ID: CC2085, Grant title: Wack CC2085)
Crick (Grant ID: CC2030, Grant title: Walport CC2030)
Crick (Grant ID: 10157, Grant title: Smith FC001157)