Moore, Daniel J2; Onoufriadis, Alexandros3; Shoemark, Amelia3; Simpson, Michael A3; zur Lage, Petra I3; de Castro, Sandra C3; Bartoloni, Lucia3; Gallone, Giuseppe3; Petridi, Stavroula3; Woollard, Wesley J3; Antony, Dinu3; Schmidts, Miriam3; Didonna, Teresa3; Makrythanasis, Periklis3; Bevillard, Jeremy3; Mongan, Nigel P3; Djakow, Jana3; Pals, Gerard3; Lucas, Jane S3; Marthin, June K3; Nielsen, Kim G1; Santoni, Federico3; Guipponi, Michel3; Hogg, Claire3; Antonarakis, Stylianos E3; Emes, Richard D3; Chung, Eddie M K3; Greene, Nicholas D E3; Blouin, Jean-Louis3; Jarman, Andrew P3; Mitchison, Hannah M3
1 Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet, The Capital Region of Denmark2 Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.3 unknown
Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T>G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects.
American Journal of Human Genetics, 2013, Vol 93, Issue 2, p. 346-56