Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 2, Pages 346-356Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.07.009
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Funding
- Gebert Foundation
- Swiss National Science Foundation [32003B_135709]
- Milena Carvajal Pro-Kartagener Foundation of Geneva
- Bodossakis Foundation
- Action Medical Research UK Clinical Training Fellowship [RTF-1411]
- Action Medical Research [GN1773, GN2101]
- Newlife Foundation for Disabled Children UK [10-11/15]
- Medical Research Council of Great Britain [MR/K018558/10]
- Biotechnology and Biological Sciences Research Council
- Medical Research Council
- [ERC 249968]
- [SNF 144082]
- Swiss National Science Foundation (SNF) [32003B_135709] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MR/K018558/1] Funding Source: UKRI
- Action Medical Research [1773, 2101] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- Medical Research Council [MR/K018558/1] Funding Source: researchfish
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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.
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