DYX1C1 is required for axonemal dynein assembly and ciliary motility

Aarti Tarkar; Niki T. Loges; Christopher E. Slagle; Richard Francis; Gerard W. Dougherty; Joel V. Tamayo; Brett Shook; Marie Cantino; Daniel Schwartz; Charlotte Jahnke; Heike Olbrich; Claudius Werner; Johanna Raidt; Petra Pennekamp; Marouan Abouhamed; Rim Hjeij; Gabriele Köhler; Matthias Griese; You Li; Kristi Lemke; Nikolas Klena; Xiaoqin Liu; George Gabriel; Kimimasa Tobita; Martine Jaspers; Lucy C. Morgan; Adam J. Shapiro; Stef J.F. Letteboer; Dorus A. Mans; Johnny L. Carson; Margaret W. Leigh; Whitney E. Wolf; Serafine Chen; Jane S. Lucas; Alexandros Onoufriadis; Vincent Plagnol; Miriam Schmidts; Karsten Boldt; Ronald Roepman; Maimoona A. Zariwala; Cecilia W. Lo; Hannah M. Mitchison; Michael R. Knowles; Rebecca D. Burdine; Joseph J. Loturco; Heymut Omran

doi:10.1038/ng.2707

DYX1C1 is required for axonemal dynein assembly and ciliary motility

Aarti Tarkar, Niki T. Loges, Christopher E. Slagle, Richard Francis, Gerard W. Dougherty, Joel V. Tamayo, Brett Shook, Marie Cantino, Daniel Schwartz, Charlotte Jahnke, Heike Olbrich, Claudius Werner, Johanna Raidt, Petra Pennekamp, Marouan Abouhamed, Rim Hjeij, Gabriele Köhler, Matthias Griese, You Li, Kristi LemkeNikolas Klena, Xiaoqin Liu, George Gabriel, Kimimasa Tobita, Martine Jaspers, Lucy C. Morgan, Adam J. Shapiro, Stef J.F. Letteboer, Dorus A. Mans, Johnny L. Carson, Margaret W. Leigh, Whitney E. Wolf, Serafine Chen, Jane S. Lucas, Alexandros Onoufriadis, Vincent Plagnol, Miriam Schmidts, Karsten Boldt, Ronald Roepman, Maimoona A. Zariwala, Cecilia W. Lo, Hannah M. Mitchison, Michael R. Knowles, Rebecca D. Burdine, Joseph J. Loturco, Heymut Omran

Molecular Biology

Research output: Contribution to journal › Article › peer-review

208 Scopus citations

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).

Original language	English (US)
Pages (from-to)	995-1003
Number of pages	9
Journal	Nature Genetics
Volume	45
Issue number	9
DOIs	https://doi.org/10.1038/ng.2707
State	Published - Sep 2013

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/ng.2707

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Tarkar, A., Loges, N. T., Slagle, C. E., Francis, R., Dougherty, G. W., Tamayo, J. V., Shook, B., Cantino, M., Schwartz, D., Jahnke, C., Olbrich, H., Werner, C., Raidt, J., Pennekamp, P., Abouhamed, M., Hjeij, R., Köhler, G., Griese, M., Li, Y., ... Omran, H. (2013). DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nature Genetics, 45(9), 995-1003. https://doi.org/10.1038/ng.2707

@article{ce49b2437e014d698cd555f1a806ff2b,

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).",

author = "Aarti Tarkar and Loges, {Niki T.} and Slagle, {Christopher E.} and Richard Francis and Dougherty, {Gerard W.} and Tamayo, {Joel V.} and Brett Shook and Marie Cantino and Daniel Schwartz and Charlotte Jahnke and Heike Olbrich and Claudius Werner and Johanna Raidt and Petra Pennekamp and Marouan Abouhamed and Rim Hjeij and Gabriele K{\"o}hler and Matthias Griese and You Li and Kristi Lemke and Nikolas Klena and Xiaoqin Liu and George Gabriel and Kimimasa Tobita and Martine Jaspers and Morgan, {Lucy C.} and Shapiro, {Adam J.} and Letteboer, {Stef J.F.} and Mans, {Dorus A.} and Carson, {Johnny L.} and Leigh, {Margaret W.} and Wolf, {Whitney E.} and Serafine Chen and Lucas, {Jane S.} and Alexandros Onoufriadis and Vincent Plagnol and Miriam Schmidts and Karsten Boldt and Ronald Roepman and Zariwala, {Maimoona A.} and Lo, {Cecilia W.} and Mitchison, {Hannah M.} and Knowles, {Michael R.} and Burdine, {Rebecca D.} and Loturco, {Joseph J.} and Heymut Omran",

note = "Funding Information: We thank the individuals with PCD and their families for participating in this study, the German patient support group Kartagener Syndrom und Primaere Ciliaere Dyskinesie and the US PCD foundation. We thank S. King (University of Connecticut Health Center) for providing antibodies and for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft (DFG Om 6/4), by the Interdisziplinaeres Zentrum f{\"u}r Klinische Forschung (IZKF) M{\"u}nster (H. Omran), by the European Community{\textquoteright}s Seventh Framework Programme FP7/2009, under grant agreement 241955, SYSCILIA (R.R. and H. Omran), and BESTCILIA, under grant agreement 305404 (H. Omran), by the Netherlands Organization for Scientific Research (NWO; Vidi-91786396 and Vici-016.130.664) (R.R.) and by grants from the US National Institutes of Health (NIH; R01 HD055655, R01 MH056524 and P01 HD057853 (J.J.L.): research grant 5 U54 HL096458-06 (M.R.K., M.W.L., J.L.C. and M.A.Z.); NHLBI grant 5 R01HL071798 (M.R.K. and M.A.Z.); National Institute of Child Health and Human Development (NICHD) grant 2 R01HD048584 (C.E.S., J.V.T., S.C. and R.D.B.); NIH grant U01HL098180 (C.W.L.); and American Heart Association fellowship (Y.L.). The work was also supported by Newlife Foundation grant 10/11/15 (H.M.M.) and Action Medical Research grant RTF1411 (M.S.). UK10K was funded by the Wellcome Trust (award WT091310). This work was supported in part by US NIH grant UL1 TR000083 from the National Center for Advancing Translational Sciences (NCATS).",

year = "2013",

month = sep,

doi = "10.1038/ng.2707",

language = "English (US)",

volume = "45",

pages = "995--1003",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Tarkar, A, Loges, NT, Slagle, CE, Francis, R, Dougherty, GW, Tamayo, JV, Shook, B, Cantino, M, Schwartz, D, Jahnke, C, Olbrich, H, Werner, C, Raidt, J, Pennekamp, P, Abouhamed, M, Hjeij, R, Köhler, G, Griese, M, Li, Y, Lemke, K, Klena, N, Liu, X, Gabriel, G, Tobita, K, Jaspers, M, Morgan, LC, Shapiro, AJ, Letteboer, SJF, Mans, DA, Carson, JL, Leigh, MW, Wolf, WE, Chen, S, Lucas, JS, Onoufriadis, A, Plagnol, V, Schmidts, M, Boldt, K, Roepman, R, Zariwala, MA, Lo, CW, Mitchison, HM, Knowles, MR, Burdine, RD, Loturco, JJ & Omran, H 2013, 'DYX1C1 is required for axonemal dynein assembly and ciliary motility', Nature Genetics, vol. 45, no. 9, pp. 995-1003. https://doi.org/10.1038/ng.2707

TY - JOUR

T1 - DYX1C1 is required for axonemal dynein assembly and ciliary motility

AU - Tarkar, Aarti

AU - Loges, Niki T.

AU - Slagle, Christopher E.

AU - Francis, Richard

AU - Dougherty, Gerard W.

AU - Tamayo, Joel V.

AU - Shook, Brett

AU - Cantino, Marie

AU - Schwartz, Daniel

AU - Jahnke, Charlotte

AU - Olbrich, Heike

AU - Werner, Claudius

AU - Raidt, Johanna

AU - Pennekamp, Petra

AU - Abouhamed, Marouan

AU - Hjeij, Rim

AU - Köhler, Gabriele

AU - Griese, Matthias

AU - Li, You

AU - Lemke, Kristi

AU - Klena, Nikolas

AU - Liu, Xiaoqin

AU - Gabriel, George

AU - Tobita, Kimimasa

AU - Jaspers, Martine

AU - Morgan, Lucy C.

AU - Shapiro, Adam J.

AU - Letteboer, Stef J.F.

AU - Mans, Dorus A.

AU - Carson, Johnny L.

AU - Leigh, Margaret W.

AU - Wolf, Whitney E.

AU - Chen, Serafine

AU - Lucas, Jane S.

AU - Onoufriadis, Alexandros

AU - Plagnol, Vincent

AU - Schmidts, Miriam

AU - Boldt, Karsten

AU - Roepman, Ronald

AU - Zariwala, Maimoona A.

AU - Lo, Cecilia W.

AU - Mitchison, Hannah M.

AU - Knowles, Michael R.

AU - Burdine, Rebecca D.

AU - Loturco, Joseph J.

AU - Omran, Heymut

N1 - Funding Information: We thank the individuals with PCD and their families for participating in this study, the German patient support group Kartagener Syndrom und Primaere Ciliaere Dyskinesie and the US PCD foundation. We thank S. King (University of Connecticut Health Center) for providing antibodies and for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft (DFG Om 6/4), by the Interdisziplinaeres Zentrum für Klinische Forschung (IZKF) Münster (H. Omran), by the European Community’s Seventh Framework Programme FP7/2009, under grant agreement 241955, SYSCILIA (R.R. and H. Omran), and BESTCILIA, under grant agreement 305404 (H. Omran), by the Netherlands Organization for Scientific Research (NWO; Vidi-91786396 and Vici-016.130.664) (R.R.) and by grants from the US National Institutes of Health (NIH; R01 HD055655, R01 MH056524 and P01 HD057853 (J.J.L.): research grant 5 U54 HL096458-06 (M.R.K., M.W.L., J.L.C. and M.A.Z.); NHLBI grant 5 R01HL071798 (M.R.K. and M.A.Z.); National Institute of Child Health and Human Development (NICHD) grant 2 R01HD048584 (C.E.S., J.V.T., S.C. and R.D.B.); NIH grant U01HL098180 (C.W.L.); and American Heart Association fellowship (Y.L.). The work was also supported by Newlife Foundation grant 10/11/15 (H.M.M.) and Action Medical Research grant RTF1411 (M.S.). UK10K was funded by the Wellcome Trust (award WT091310). This work was supported in part by US NIH grant UL1 TR000083 from the National Center for Advancing Translational Sciences (NCATS).

PY - 2013/9

Y1 - 2013/9

N2 - 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).

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84883446171&partnerID=8YFLogxK

U2 - 10.1038/ng.2707

DO - 10.1038/ng.2707

M3 - Article

C2 - 23872636

AN - SCOPUS:84883446171

SN - 1061-4036

VL - 45

SP - 995

EP - 1003

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

DYX1C1 is required for axonemal dynein assembly and ciliary motility

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