ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6

Maimoona A. Zariwala; Heon Yung Gee; Małgorzata Kurkowiak; Dalal A. Al-Mutairi; Margaret W. Leigh; Toby W. Hurd; Rim Hjeij; Sharon D. Dell; Moumita Chaki; Gerard W. Dougherty; Mohamed Adan; Philip C. Spear; Julian Esteve-Rudd; Niki T. Loges; Margaret Rosenfeld; Katrina A. Diaz; Heike Olbrich; Whitney E. Wolf; Eamonn Sheridan; Trevor F.C. Batten; Jan Halbritter; Jonathan D. Porath; Stefan Kohl; Svjetlana Lovric; Daw Yang Hwang; Jessica E. Pittman; Kimberlie A. Burns; Thomas W. Ferkol; Scott D. Sagel; Kenneth N. Olivier; Lucy C. Morgan; Claudius Werner; Johanna Raidt; Petra Pennekamp; Zhaoxia Sun; Weibin Zhou; Rannar Airik; Sivakumar Natarajan; Susan J. Allen; Israel Amirav; Dagmar Wieczorek; Kerstin Landwehr; Kim Nielsen; Nicolaus Schwerk; Jadranka Sertic; Gabriele Köhler; Joseph Washburn; Shawn Levy; Shuling Fan; Cordula Koerner-Rettberg; Serge Amselem; David S. Williams; Brian J. Mitchell; Iain A. Drummond; Edgar A. Otto; Heymut Omran; Michael R. Knowles; Friedhelm Hildebrandt

doi:10.1016/j.ajhg.2013.06.007

ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6

Maimoona A. Zariwala, Heon Yung Gee, Małgorzata Kurkowiak, Dalal A. Al-Mutairi, Margaret W. Leigh, Toby W. Hurd, Rim Hjeij, Sharon D. Dell, Moumita Chaki, Gerard W. Dougherty, Mohamed Adan, Philip C. Spear, Julian Esteve-Rudd, Niki T. Loges, Margaret Rosenfeld, Katrina A. Diaz, Heike Olbrich, Whitney E. Wolf, Eamonn Sheridan, Trevor F.C. BattenJan Halbritter, Jonathan D. Porath, Stefan Kohl, Svjetlana Lovric, Daw Yang Hwang, Jessica E. Pittman, Kimberlie A. Burns, Thomas W. Ferkol, Scott D. Sagel, Kenneth N. Olivier, Lucy C. Morgan, Claudius Werner, Johanna Raidt, Petra Pennekamp, Zhaoxia Sun, Weibin Zhou, Rannar Airik, Sivakumar Natarajan, Susan J. Allen, Israel Amirav, Dagmar Wieczorek, Kerstin Landwehr, Kim Nielsen, Nicolaus Schwerk, Jadranka Sertic, Gabriele Köhler, Joseph Washburn, Shawn Levy, Shuling Fan, Cordula Koerner-Rettberg, Serge Amselem, David S. Williams, Brian J. Mitchell, Iain A. Drummond, Edgar A. Otto, Heymut Omran, Michael R. Knowles, Friedhelm Hildebrandt

Department of Pharmacology

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

148 Citations (Scopus)

Abstract

Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

Original language	English
Pages (from-to)	336-345
Number of pages	10
Journal	American Journal of Human Genetics
Volume	93
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2013.06.007
Publication status	Published - 2013 Aug 8

Bibliographical note

Funding Information:
We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.” This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project “Studies of nucleic acids and proteins—from basic to applied research,” sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF Münster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data .

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2013.06.007

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Zariwala, M. A., Gee, H. Y., Kurkowiak, M., Al-Mutairi, D. A., Leigh, M. W., Hurd, T. W., Hjeij, R., Dell, S. D., Chaki, M., Dougherty, G. W., Adan, M., Spear, P. C., Esteve-Rudd, J., Loges, N. T., Rosenfeld, M., Diaz, K. A., Olbrich, H., Wolf, W. E., Sheridan, E., ... Hildebrandt, F. (2013). ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. American Journal of Human Genetics, 93(2), 336-345. https://doi.org/10.1016/j.ajhg.2013.06.007

@article{cba071e881344ed88abdf9ff112f8ccf,

title = "ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6",

abstract = "Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.",

author = "Zariwala, {Maimoona A.} and Gee, {Heon Yung} and Ma{\l}gorzata Kurkowiak and Al-Mutairi, {Dalal A.} and Leigh, {Margaret W.} and Hurd, {Toby W.} and Rim Hjeij and Dell, {Sharon D.} and Moumita Chaki and Dougherty, {Gerard W.} and Mohamed Adan and Spear, {Philip C.} and Julian Esteve-Rudd and Loges, {Niki T.} and Margaret Rosenfeld and Diaz, {Katrina A.} and Heike Olbrich and Wolf, {Whitney E.} and Eamonn Sheridan and Batten, {Trevor F.C.} and Jan Halbritter and Porath, {Jonathan D.} and Stefan Kohl and Svjetlana Lovric and Hwang, {Daw Yang} and Pittman, {Jessica E.} and Burns, {Kimberlie A.} and Ferkol, {Thomas W.} and Sagel, {Scott D.} and Olivier, {Kenneth N.} and Morgan, {Lucy C.} and Claudius Werner and Johanna Raidt and Petra Pennekamp and Zhaoxia Sun and Weibin Zhou and Rannar Airik and Sivakumar Natarajan and Allen, {Susan J.} and Israel Amirav and Dagmar Wieczorek and Kerstin Landwehr and Kim Nielsen and Nicolaus Schwerk and Jadranka Sertic and Gabriele K{\"o}hler and Joseph Washburn and Shawn Levy and Shuling Fan and Cordula Koerner-Rettberg and Serge Amselem and Williams, {David S.} and Mitchell, {Brian J.} and Drummond, {Iain A.} and Otto, {Edgar A.} and Heymut Omran and Knowles, {Michael R.} and Friedhelm Hildebrandt",

note = "Funding Information: We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.” This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project “Studies of nucleic acids and proteins—from basic to applied research,” sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF M{\"u}nster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data . ",

year = "2013",

month = aug,

day = "8",

doi = "10.1016/j.ajhg.2013.06.007",

language = "English",

volume = "93",

pages = "336--345",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Zariwala, MA, Gee, HY, Kurkowiak, M, Al-Mutairi, DA, Leigh, MW, Hurd, TW, Hjeij, R, Dell, SD, Chaki, M, Dougherty, GW, Adan, M, Spear, PC, Esteve-Rudd, J, Loges, NT, Rosenfeld, M, Diaz, KA, Olbrich, H, Wolf, WE, Sheridan, E, Batten, TFC, Halbritter, J, Porath, JD, Kohl, S, Lovric, S, Hwang, DY, Pittman, JE, Burns, KA, Ferkol, TW, Sagel, SD, Olivier, KN, Morgan, LC, Werner, C, Raidt, J, Pennekamp, P, Sun, Z, Zhou, W, Airik, R, Natarajan, S, Allen, SJ, Amirav, I, Wieczorek, D, Landwehr, K, Nielsen, K, Schwerk, N, Sertic, J, Köhler, G, Washburn, J, Levy, S, Fan, S, Koerner-Rettberg, C, Amselem, S, Williams, DS, Mitchell, BJ, Drummond, IA, Otto, EA, Omran, H, Knowles, MR & Hildebrandt, F 2013, 'ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6', American Journal of Human Genetics, vol. 93, no. 2, pp. 336-345. https://doi.org/10.1016/j.ajhg.2013.06.007

TY - JOUR

T1 - ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6

AU - Zariwala, Maimoona A.

AU - Gee, Heon Yung

AU - Kurkowiak, Małgorzata

AU - Al-Mutairi, Dalal A.

AU - Leigh, Margaret W.

AU - Hurd, Toby W.

AU - Hjeij, Rim

AU - Dell, Sharon D.

AU - Chaki, Moumita

AU - Dougherty, Gerard W.

AU - Adan, Mohamed

AU - Spear, Philip C.

AU - Esteve-Rudd, Julian

AU - Loges, Niki T.

AU - Rosenfeld, Margaret

AU - Diaz, Katrina A.

AU - Olbrich, Heike

AU - Wolf, Whitney E.

AU - Sheridan, Eamonn

AU - Batten, Trevor F.C.

AU - Halbritter, Jan

AU - Porath, Jonathan D.

AU - Kohl, Stefan

AU - Lovric, Svjetlana

AU - Hwang, Daw Yang

AU - Pittman, Jessica E.

AU - Burns, Kimberlie A.

AU - Ferkol, Thomas W.

AU - Sagel, Scott D.

AU - Olivier, Kenneth N.

AU - Morgan, Lucy C.

AU - Werner, Claudius

AU - Raidt, Johanna

AU - Pennekamp, Petra

AU - Sun, Zhaoxia

AU - Zhou, Weibin

AU - Airik, Rannar

AU - Natarajan, Sivakumar

AU - Allen, Susan J.

AU - Amirav, Israel

AU - Wieczorek, Dagmar

AU - Landwehr, Kerstin

AU - Nielsen, Kim

AU - Schwerk, Nicolaus

AU - Sertic, Jadranka

AU - Köhler, Gabriele

AU - Washburn, Joseph

AU - Levy, Shawn

AU - Fan, Shuling

AU - Koerner-Rettberg, Cordula

AU - Amselem, Serge

AU - Williams, David S.

AU - Mitchell, Brian J.

AU - Drummond, Iain A.

AU - Otto, Edgar A.

AU - Omran, Heymut

AU - Knowles, Michael R.

AU - Hildebrandt, Friedhelm

N1 - Funding Information: We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group “Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.” This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project “Studies of nucleic acids and proteins—from basic to applied research,” sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF Münster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data .

PY - 2013/8/8

Y1 - 2013/8/8

N2 - Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

AB - Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility. Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally, ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.

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UR - http://www.scopus.com/inward/citedby.url?scp=84881664454&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2013.06.007

DO - 10.1016/j.ajhg.2013.06.007

M3 - Article

C2 - 23891469

AN - SCOPUS:84881664454

SN - 0002-9297

VL - 93

SP - 336

EP - 345

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6

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