title: DYX1C1 is required for axonemal dynein assembly and ciliary motility.
abstract: 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).
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA.
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authors.forename: Niki T
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authors.forename: Xiaoqin
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authors.forename: Kimimasa
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authors.lastname: Letteboer
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authors.forename: Margaret W
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authors.lastname: Wolf
authors.forename: Serafine
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authors.lastname: Chen
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authors.initials: JS
authors.lastname: Lucas
authors.forename: Alexandros
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authors.lastname: Onoufriadis
authors.forename: Vincent
authors.identifier: 0000000255979215
authors.initials: V
authors.lastname: Plagnol
authors.forename: Miriam
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authors.lastname: Schmidts
authors.forename: Karsten
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authors.lastname: Boldt
authors.forename: Ronald
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authors.lastname: Roepman
authors.forename: Maimoona A
authors.initials: MA
authors.lastname: Zariwala
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Burdine
authors.forename: Joseph J
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authors.lastname: Loturco
authors.forename: Heymut
authors.initials: H
authors.lastname: Omran
mesh_terms: D000818:Animals; D056444:Axonemal Dyneins / Q000235:genetics* / Q000378:metabolism*; D002923:Cilia / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004805:Ependyma / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D023061:Gene Order; D018390:Gene Targeting; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007619:Kartagener Syndrome / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish
chemical_list: C584544:DYX1C1 protein, mouse; D009419:Nerve Tissue Proteins; D056444:Axonemal Dyneins