CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms

被引:186
作者
Panizzi, Jennifer R. [1 ,2 ]
Becker-Heck, Anita [3 ,4 ]
Castleman, Victoria H. [5 ]
Al-Mutairi, Dalal A. [6 ,7 ]
Liu, Yan [1 ]
Loges, Niki T. [4 ]
Pathak, Narendra [1 ,2 ]
Austin-Tse, Christina [8 ]
Sheridan, Eamonn [6 ]
Schmidts, Miriam
Olbrich, Heike [4 ]
Werner, Claudius [4 ]
Haeffner, Karsten
Hellman, Nathan [1 ,2 ]
Chodhari, Rahul [9 ]
Gupta, Amar [1 ]
Kramer-Zucker, Albrecht [10 ]
Olale, Felix [11 ]
Burdine, Rebecca D. [12 ]
Schier, Alexander F. [13 ]
O'Callaghan, Christopher [14 ]
Chung, Eddie M. K. [9 ]
Reinhardt, Richard [15 ]
Mitchison, Hannah M.
King, Stephen M. [16 ]
Omran, Heymut [4 ]
Drummond, Iain A. [1 ,2 ]
机构
[1] Massachusetts Gen Hosp, Div Neurol, Charlestown, MA 02129 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[3] Univ Hosp Freiburg, Dept Pediat, Freiburg, Germany
[4] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed Allgemeine Pae, Munster, Germany
[5] UCL, Mol Med Unit, Inst Child Hlth, London, England
[6] St James Univ Hosp, Leeds Inst Mol Med, Leeds, W Yorkshire, England
[7] Kuwait Univ, Fac Med, Dept Pathol, Kuwait, Kuwait
[8] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA
[9] UCL, Inst Child Hlth, Gen & Adolescent Paediat Unit, London, England
[10] Univ Hosp Freiburg, Div Renal, Freiburg, Germany
[11] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY USA
[12] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA
[13] Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA
[14] Univ Leicester, Dept Infect Immun & Inflammat, Leicester, Leics, England
[15] Max Planck Inst Plant Breeding Res, Genome Ctr Cologne, Cologne, Germany
[16] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT USA
基金
英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;
关键词
ZEBRAFISH PRONEPHROS; PROTEIN; REQUIREMENT; EXPRESSION; ENCODES; GENES;
D O I
10.1038/ng.2277
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cilia are essential for fertilization, respiratory clearance, cerebrospinal fluid circulation and establishing laterality(1). Cilia motility defects cause primary ciliary dyskinesia (PCD, MIM244400), a disorder affecting 1: 15,000-30,000 births. Cilia motility requires the assembly of multisubunit dynein arms that drive ciliary bending(2). Despite progress in understanding the genetic basis of PCD, mutations remain to be identified for several PCD-linked loci(3). Here we show that the zebrafish cilia paralysis mutant schmalhans (smh(tn222)) encodes the coiled-coil domain containing 103 protein (Ccdc103), a foxj1a-regulated gene product. Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103. Dynein arm assembly in smh mutant zebrafish was rescued by wild-type but not mutant human CCDC103. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.
引用
收藏
页码:714 / U148
页数:8
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