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Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia

Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia
Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia
Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T>G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects.
0002-9297
346-356
Moore, Daniel J.
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Onoufriadis, Alexandros
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Shoemark, Amelia
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Simpson, Michael A.
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Zur Lage, Petra I.
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de Castro, Sandra C.
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Bartoloni, Lucia
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Gallone, Giuseppe
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Petridi, Stavroula
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Woollard, Wesley J.
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Antony, Dinu
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Schmidts, Miriam
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Didonna, Teresa
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Makrythanasis, Periklis
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Bevillard, Jeremy
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Mongan, Nigel P.
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Djakow, Jana
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Pals, Gerard
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Lucas, Jane S.
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Marthin, June K.
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Nielsen, Kim G.
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Santoni, Federico
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Guipponi, Michel
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Hogg, Claire
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Antonarakis, Stylianos E.
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Emes, Richard D.
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Chung, Eddie M. K.
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Greene, Nicholas D. E.
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Blouin, Jean-Louis
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Jarman, Andrew P.
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Mitchison, Hannah M.
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Moore, Daniel J.
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Onoufriadis, Alexandros
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Shoemark, Amelia
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Simpson, Michael A.
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Zur Lage, Petra I.
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de Castro, Sandra C.
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Bartoloni, Lucia
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Gallone, Giuseppe
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Petridi, Stavroula
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Woollard, Wesley J.
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Antony, Dinu
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Schmidts, Miriam
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Didonna, Teresa
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Makrythanasis, Periklis
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Bevillard, Jeremy
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Mongan, Nigel P.
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Djakow, Jana
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Pals, Gerard
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Lucas, Jane S.
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Marthin, June K.
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Nielsen, Kim G.
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Guipponi, Michel
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Hogg, Claire
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Antonarakis, Stylianos E.
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Emes, Richard D.
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Chung, Eddie M. K.
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Greene, Nicholas D. E.
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Blouin, Jean-Louis
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Jarman, Andrew P.
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Mitchison, Hannah M.
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Moore, Daniel J., Onoufriadis, Alexandros, Shoemark, Amelia, Simpson, Michael A., Zur Lage, Petra I., de Castro, Sandra C., Bartoloni, Lucia, Gallone, Giuseppe, Petridi, Stavroula, Woollard, Wesley J., Antony, Dinu, Schmidts, Miriam, Didonna, Teresa, Makrythanasis, Periklis, Bevillard, Jeremy, Mongan, Nigel P., Djakow, Jana, Pals, Gerard, Lucas, Jane S., Marthin, June K., Nielsen, Kim G., Santoni, Federico, Guipponi, Michel, Hogg, Claire, Antonarakis, Stylianos E., Emes, Richard D., Chung, Eddie M. K., Greene, Nicholas D. E., Blouin, Jean-Louis, Jarman, Andrew P. and Mitchison, Hannah M. (2013) Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. The American Journal of Human Genetics, 93 (2), 346-356. (doi:10.1016/j.ajhg.2013.07.009). (PMID:23891471)

Record type: Article

Abstract

Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combined IDA and ODA defects, we found that 6/38 (16%) carried biallelic mutations in the conserved zinc-finger gene BLU (ZMYND10). ZMYND10 mutations conferred dynein-arm loss seen at the ultrastructural and immunofluorescence level and complete cilia immotility, except in hypomorphic p.Val16Gly (c.47T>G) homozygote individuals, whose cilia retained a stiff and slowed beat. In mice, Zmynd10 mRNA is restricted to regions containing motile cilia. In a Drosophila model of PCD, Zmynd10 is exclusively expressed in cells with motile cilia: chordotonal sensory neurons and sperm. In these cells, P-element-mediated gene silencing caused IDA and ODA defects, proprioception deficits, and sterility due to immotile sperm. Drosophila Zmynd10 with an equivalent c.47T>G (p.Val16Gly) missense change rescued mutant male sterility less than the wild-type did. Tagged Drosophila ZMYND10 is localized primarily to the cytoplasm, and human ZMYND10 interacts with LRRC6, another cytoplasmically localized protein altered in PCD. Using a fly model of PCD, we conclude that ZMYND10 is a cytoplasmic protein required for IDA and ODA assembly and that its variants cause ciliary dysmotility and PCD with laterality defects.

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e-pub ahead of print date: 24 July 2013
Published date: 8 August 2013
Organisations: Clinical & Experimental Sciences

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Local EPrints ID: 355202
URI: http://eprints.soton.ac.uk/id/eprint/355202
ISSN: 0002-9297
PURE UUID: 5b061f09-cf2f-4230-afaa-e9162838eb5b

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Date deposited: 14 Aug 2013 11:34
Last modified: 16 Jul 2019 21:27

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Contributors

Author: Daniel J. Moore
Author: Alexandros Onoufriadis
Author: Amelia Shoemark
Author: Michael A. Simpson
Author: Petra I. Zur Lage
Author: Sandra C. de Castro
Author: Lucia Bartoloni
Author: Giuseppe Gallone
Author: Stavroula Petridi
Author: Wesley J. Woollard
Author: Dinu Antony
Author: Miriam Schmidts
Author: Teresa Didonna
Author: Periklis Makrythanasis
Author: Jeremy Bevillard
Author: Nigel P. Mongan
Author: Jana Djakow
Author: Gerard Pals
Author: Jane S. Lucas
Author: June K. Marthin
Author: Kim G. Nielsen
Author: Federico Santoni
Author: Michel Guipponi
Author: Claire Hogg
Author: Stylianos E. Antonarakis
Author: Richard D. Emes
Author: Eddie M. K. Chung
Author: Nicholas D. E. Greene
Author: Jean-Louis Blouin
Author: Andrew P. Jarman
Author: Hannah M. Mitchison

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