Journal
NATURE GENETICS
Volume 45, Issue 9, Pages 995-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2707
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Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [Om 6/4]
- Interdisziplinaeres Zentrum fur Klinische Forschung (IZKF) Munster
- European Community's Seventh Framework Programme FP7 [241955]
- SYSCILIA
- BESTCILIA [305404]
- Netherlands Organization for Scientific Research (NWO) [Vidi-91786396, Vici-016.130.664]
- US National Institutes of Health (NIH) [R01 HD055655, R01 MH056524, P01 HD057853, 5 U54 HL096458-06]
- NHLBI grant [5 R01HL071798]
- National Institute of Child Health and Human Development (NICHD) grant [2 R01HD048584]
- NIH grant [U01HL098180]
- American Heart Association fellowship
- Newlife Foundation grant [10/11/15]
- Action Medical Research grant [RTF1411]
- Wellcome Trust [WT091310]
- US NIH grant from the National Center for Advancing Translational Sciences (NCATS) [UL1 TR000083]
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268] Funding Source: researchfish
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DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).
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