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 & 38 others 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

Research output: Contribution to journalArticle

81 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 languageEnglish (US)
Pages (from-to)336-345
Number of pages10
JournalAmerican Journal of Human Genetics
Volume93
Issue number2
DOIs
StatePublished - Aug 8 2013

Fingerprint

Kartagener Syndrome
Mutation
Cilia
Cystic Kidney Diseases
Exome
Centrioles
Otolithic Membrane
Male Infertility
Zebrafish
Xenopus
Paralysis
Respiratory Tract Infections
Proteins
Animal Models

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Zariwala, M. A., Gee, H. Y., Kurkowiak, M., Al-Mutairi, D. A., Leigh, M. W., Hurd, T. W., ... 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

ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. / Zariwala, Maimoona A.; Gee, Heon Yung; Kurkowiak, Małgorzata; Al-Mutairi, Dalal A.; Leigh, Margaret W.; Hurd, Toby W.; Hjeij, Rim; Dell, Sharon D.; Chaki, Moumita; Dougherty, Gerard W.; Adan, Mohamed; Spear, Philip C.; Esteve-Rudd, Julian; Loges, Niki T.; Rosenfeld, Margaret; Diaz, Katrina A.; Olbrich, Heike; Wolf, Whitney E.; Sheridan, Eamonn; Batten, Trevor F C; Halbritter, Jan; Porath, Jonathan D.; Kohl, Stefan; Lovric, Svjetlana; Hwang, Daw Yang; Pittman, Jessica E.; Burns, Kimberlie A.; Ferkol, Thomas W.; Sagel, Scott D.; Olivier, Kenneth N.; Morgan, Lucy C.; Werner, Claudius; Raidt, Johanna; Pennekamp, Petra; Sun, Zhaoxia; Zhou, Weibin; Airik, Rannar; Natarajan, Sivakumar; Allen, Susan J.; Amirav, Israel; Wieczorek, Dagmar; Landwehr, Kerstin; Nielsen, Kim; Schwerk, Nicolaus; Sertic, Jadranka; Köhler, Gabriele; Washburn, Joseph; Levy, Shawn; Fan, Shuling; Koerner-Rettberg, Cordula; Amselem, Serge; Williams, David S.; Mitchell, Brian J.; Drummond, Iain A.; Otto, Edgar A.; Omran, Heymut; Knowles, Michael R.; Hildebrandt, Friedhelm.

In: American Journal of Human Genetics, Vol. 93, No. 2, 08.08.2013, p. 336-345.

Research output: Contribution to journalArticle

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
Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW et al. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. American Journal of Human Genetics. 2013 Aug 8;93(2):336-345. https://doi.org/10.1016/j.ajhg.2013.06.007
Zariwala, Maimoona A. ; Gee, Heon Yung ; Kurkowiak, Małgorzata ; Al-Mutairi, Dalal A. ; Leigh, Margaret W. ; Hurd, Toby W. ; Hjeij, Rim ; Dell, Sharon D. ; Chaki, Moumita ; Dougherty, Gerard W. ; Adan, Mohamed ; Spear, Philip C. ; Esteve-Rudd, Julian ; Loges, Niki T. ; Rosenfeld, Margaret ; Diaz, Katrina A. ; Olbrich, Heike ; Wolf, Whitney E. ; Sheridan, Eamonn ; Batten, Trevor F C ; Halbritter, Jan ; Porath, Jonathan D. ; Kohl, Stefan ; Lovric, Svjetlana ; Hwang, Daw Yang ; Pittman, Jessica E. ; Burns, Kimberlie A. ; Ferkol, Thomas W. ; Sagel, Scott D. ; Olivier, Kenneth N. ; Morgan, Lucy C. ; Werner, Claudius ; Raidt, Johanna ; Pennekamp, Petra ; Sun, Zhaoxia ; Zhou, Weibin ; Airik, Rannar ; Natarajan, Sivakumar ; Allen, Susan J. ; Amirav, Israel ; Wieczorek, Dagmar ; Landwehr, Kerstin ; Nielsen, Kim ; Schwerk, Nicolaus ; Sertic, Jadranka ; Köhler, Gabriele ; Washburn, Joseph ; Levy, Shawn ; Fan, Shuling ; Koerner-Rettberg, Cordula ; Amselem, Serge ; Williams, David S. ; Mitchell, Brian J. ; Drummond, Iain A. ; Otto, Edgar A. ; Omran, Heymut ; Knowles, Michael R. ; Hildebrandt, Friedhelm. / ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 2. pp. 336-345.
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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.",
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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.

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AU - Drummond, Iain A.

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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.

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