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Am J Hum Genet August 8, 2013; 93 (2): 336-45.

ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.

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 TF , 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 .

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.

PubMed ID: 23891469
PMC ID: PMC3738827
Article link: Am J Hum Genet
Grant support: [+]
Genes referenced: actl6a ccdc103 ccdc39 ccdc40 cetn4 dnah5 dnali1 lrrc6 mbd1 pcbd1 pcm1 zmynd10
GO keywords: cilium assembly

Disease Ontology terms: primary ciliary dyskinesia 22

Article Images: [+] show captions
References [+] :
Albee, Identification of cilia genes that affect cell-cycle progression using whole-genome transcriptome analysis in Chlamydomonas reinhardtti. 2013, Pubmed

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