title: Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia.
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.
authors.affiliation: Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Moore
authors.forename: Alexandros
authors.initials: A
authors.lastname: Onoufriadis
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Petra I
authors.initials: PI
authors.lastname: zur Lage
authors.forename: Sandra C
authors.initials: SC
authors.lastname: de Castro
authors.forename: Lucia
authors.initials: L
authors.lastname: Bartoloni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gallone
authors.forename: Stavroula
authors.initials: S
authors.lastname: Petridi
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Woollard
authors.forename: Dinu
authors.initials: D
authors.lastname: Antony
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.forename: Teresa
authors.initials: T
authors.lastname: Didonna
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bevillard
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.forename: Jana
authors.initials: J
authors.lastname: Djakow
authors.forename: Gerard
authors.initials: G
authors.lastname: Pals
authors.forename: Jane S
authors.initials: JS
authors.lastname: Lucas
authors.forename: June K
authors.initials: JK
authors.lastname: Marthin
authors.forename: Kim G
authors.initials: KG
authors.lastname: Nielsen
authors.forename: Federico
authors.initials: F
authors.lastname: Santoni
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Claire
authors.initials: C
authors.lastname: Hogg
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jarman
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D000818:Animals; D054468:Axoneme / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002923:Cilia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004398:Dyneins / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007619:Kartagener Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D004398:Dyneins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C485849:DNAAF11 protein, human; C472720:ZMYND10 protein, human
references.citation: Nat Genet. 2002 Feb;30(2):143-4
references.pmid: 11788826
references.citation: PLoS One. 2011;6(12):e27822
references.pmid: 22145020
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3336-41
references.pmid: 17360648
references.citation: Semin Cell Dev Biol. 2011 Sep;22(7):749-58
references.pmid: 21854863
references.citation: Hum Mol Genet. 2002 May 15;11(10):1215-8
references.pmid: 12015281
references.citation: Am J Hum Genet. 2011 May 13;88(5):599-607
references.pmid: 21496787
references.citation: Nat Genet. 2008 Dec;40(12):1454-60
references.pmid: 19011629
references.citation: Nature. 2005 Oct 20;437(7062):1173-8
references.pmid: 16189514
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
references.pmid: 17955020
references.citation: Mol Biol Cell. 2013 Apr;24(8):1134-52
references.pmid: 23427265
references.citation: Nat Struct Biol. 1998 Aug;5(8):677-8
references.pmid: 9699628
references.citation: J Biol Chem. 1999 Sep 24;274(39):27439-47
references.pmid: 10488076
references.citation: Pediatr Pulmonol. 2013 Apr;48(4):352-63
references.pmid: 22888088
references.citation: Nature. 2006 Mar 9;440(7081):224-7
references.pmid: 16525475
references.citation: Nat Genet. 2012 Mar 04;44(4):381-9, S1-2
references.pmid: 22387996
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):325-30
references.pmid: 15623551
references.citation: Hum Genet. 2011 Mar;129(3):283-93
references.pmid: 21136274
references.citation: Am J Respir Cell Mol Biol. 2007 Aug;37(2):169-85
references.pmid: 17413031
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Eur J Hum Genet. 2000 Feb;8(2):109-18
references.pmid: 10757642
references.citation: Curr Biol. 2008 Jun 24;18(12):911-4
references.pmid: 18571413
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20305-10
references.pmid: 21059936
references.citation: Nat Genet. 2008 Dec;40(12):1445-53
references.pmid: 19011630
references.citation: Am J Hum Genet. 2012 Oct 5;91(4):685-93
references.pmid: 23040496
references.citation: Am J Hum Genet. 1999 Dec;65(6):1508-19
references.pmid: 10577904
references.citation: Am J Hum Genet. 2012 Oct 5;91(4):672-84
references.pmid: 23022101
references.citation: Cell. 2012 Aug 31;150(5):1042-54
references.pmid: 22939627
references.citation: Cytoskeleton (Hoboken). 2011 Jan;68(1):1-7
references.pmid: 21069788
references.citation: J Neurosci. 2000 Aug 15;20(16):5981-8
references.pmid: 10934246
references.citation: PLoS Biol. 2011 Jan 04;9(1):e1000568
references.pmid: 21283833
references.citation: Am J Hum Genet. 2013 Jan 10;92(1):88-98
references.pmid: 23261303
references.citation: Nature. 2008 Dec 4;456(7222):611-6
references.pmid: 19052621
references.citation: Nat Genet. 2011 Jan;43(1):79-84
references.pmid: 21131974
references.citation: Eur Respir J. 2009 Dec;34(6):1264-76
references.pmid: 19948909
references.citation: J Allergy Clin Immunol. 2003 Sep;112(3):518-24
references.pmid: 13679810
references.citation: Am J Hum Genet. 2012 Nov 2;91(5):958-64
references.pmid: 23122589
references.citation: Nat Genet. 2012 May 13;44(6):714-9
references.pmid: 22581229
references.citation: Eur Respir J. 2010 May;35(5):1057-63
references.pmid: 19840971
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10282-6
references.pmid: 12142464
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5514-9
references.pmid: 12642657
references.citation: Am J Hum Genet. 2013 Jan 10;92(1):99-106
references.pmid: 23261302
references.citation: Am J Hum Genet. 2009 Feb;84(2):197-209
references.pmid: 19200523
references.citation: Thorax. 1998 Oct;53(10):894-7
references.pmid: 10193380
references.citation: Physiol Genomics. 2008 Jan 17;32(2):198-206
references.pmid: 17971504
references.citation: Oncogene. 2003 Mar 13;22(10):1580-8
references.pmid: 12629521
references.citation: Am J Hum Genet. 2009 Dec;85(6):890-6
references.pmid: 19944405
references.citation: Am J Hum Genet. 2012 Aug 10;91(2):358-64
references.pmid: 22795537
references.citation: Database (Oxford). 2009;2009:bap022
references.pmid: 20428338
references.citation: Genes Dev. 1998 Nov 1;12(21):3357-68
references.pmid: 9808623
references.citation: Am J Hum Genet. 2009 Dec;85(6):883-9
references.pmid: 19944400
references.citation: J Cell Sci. 2010 Feb 15;123(Pt 4):519-28
references.pmid: 20145000
references.citation: Development. 2002 Dec;129(23):5487-98
references.pmid: 12403718
references.citation: Am J Hum Genet. 2008 Nov;83(5):547-58
references.pmid: 18950741
references.citation: Circulation. 2007 Jun 5;115(22):2814-21
references.pmid: 17515466
references.citation: Arch Dis Child. 2007 Dec;92(12):1136-40
references.pmid: 17634184
references.citation: Science. 2003 Dec 5;302(5651):1727-36
references.pmid: 14605208
references.citation: Dev Cell. 2012 Jun 12;22(6):1221-33
references.pmid: 22698283
references.citation: Genetics. 2010 May;185(1):177-88
references.pmid: 20215474
references.citation: Nat Genet. 2013 Mar;45(3):262-8
references.pmid: 23354437
references.citation: J Clin Pathol. 2012 Mar;65(3):267-71
references.pmid: 22135026
references.citation: Development. 2009 Dec;136(23):4021-31
references.pmid: 19906869
references.citation: PLoS One. 2010 Sep 20;5(9):e12847
references.pmid: 20877461
references.citation: Bioinformatics. 2010 Mar 15;26(6):841-2
references.pmid: 20110278
references.citation: Nat Genet. 2011 Jan;43(1):72-8
references.pmid: 21131972
references.citation: PLoS One. 2010 Jun 08;5(6):e11012
references.pmid: 20543979
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D751-7
references.pmid: 23125371