Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia

Autoři: Ximena M. Bustamante-Marin aff001;  Amjad Horani aff002;  Mihaela Stoyanova aff003;  Wu-Lin Charng aff003;  Mathieu Bottier aff005;  Patrick R. Sears aff001;  Wei-Ning Yin aff001;  Leigh Anne Daniels aff001;  Hailey Bowen aff002;  Donald F. Conrad aff003;  Michael R. Knowles aff001;  Lawrence E. Ostrowski aff001;  Maimoona A. Zariwala aff008;  Susan K. Dutcher aff003
Působiště autorů: Department of Medicine, Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America aff001;  Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America aff002;  Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America aff003;  Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America aff004;  Department of Mechanical Engineering, Washington University, St. Louis, Missouri, United States of America aff005;  Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon, United States of America aff006;  Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America aff007;  Department of Pathology and Laboratory Medicine and the Marsico Lung Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America aff008
Vyšlo v časopise: Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia. PLoS Genet 16(8): e1008691. doi:10.1371/journal.pgen.1008691
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008691


Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the “g” inner dyneins (DHC7 and DHC3) and the “d” inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process.

Klíčová slova:

Cilia – Dyneins – Epithelial cells – Homozygosity – Human genetics – Motor proteins – Pathogen motility – Swimming


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