Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia

被引：147

作者：

Austin-Tse, Christina ^{[1
,2
]}

Halbritter, Jan ^{[3
]}

Zariwala, Maimoona A. ^{[4
]}

Gilberti, Renee M. ^{[5
]}

Gee, Heon Yung ^{[3
]}

Hellman, Nathan ^{[1
]}

Pathak, Narendra ^{[1
]}

Liu, Yan ^{[1
]}

Panizzi, Jennifer R. ^{[1
]}

Patel-King, Ramila S. ^{[5
]}

Tritschler, Douglas ^{[6
]}

Bower, Raqual ^{[6
]}

O'Toole, Eileen ^{[7
]}

Porath, Jonathan D. ^{[3
]}

Hurd, Toby W. ^{[8
]}

Chaki, Moumita ^{[8
]}

Diaz, Katrina A. ^{[8
]}

Kohl, Stefan ^{[3
]}

Lovric, Svjetlana ^{[3
]}

Hwang, Daw-Yang ^{[3
]}

Braun, Daniela A. ^{[3
]}

Schueler, Markus ^{[3
]}

Airik, Rannar ^{[3
]}

Otto, Edgar A. ^{[8
]}

Leigh, Margaret W. ^{[9
]}

Noone, Peadar G. ^{[9
]}

Carson, Johnny L. ^{[9
]}

Davis, Stephanie D. ^{[9
]}

Pittman, Jessica E. ^{[9
]}

Ferkol, Thomas W. ^{[10
]}

Atkinson, Jeffry J. ^{[11
]}

Olivier, Kenneth N. ^{[12
]}

Sagel, Scott D. ^{[13
]}

Dell, Sharon D. ^{[14
]}

Rosenfeld, Margaret ^{[15
,16
]}

Milla, Carlos E. ^{[17
]}

Loges, Niki T. ^{[18
]}

Omran, Heymut ^{[18
]}

Porter, Mary E. ^{[6
]}

King, Stephen M. ^{[5
]}

Knowles, Michael R. ^{[19
]}

Drummond, Iain A. ^{[1
,2
]}

Hildebrandt, Friedhelm ^{[3
,20
]}

机构：

[1] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol,Dept Genet, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA

[4] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA

[5] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA

[6] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA

[7] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder Lab Electron Microscopy Cells 3D, Boulder, CO 80309 USA

[8] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[9] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA

[10] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[11] Washington Univ, Sch Med, Div Pulm & Crit Care, St Louis, MO 63110 USA

[12] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA

[13] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA

[14] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada

[15] Childrens Hosp, Seattle, WA 98105 USA

[16] Univ Washington, Seattle, WA 98105 USA

[17] Stanford Univ, Dept Pediat, Stanford, CA 94304 USA

[18] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany

[19] Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC 27599 USA

[20] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 93卷 / 04期

基金：

美国国家卫生研究院;

关键词：

DYNEIN REGULATORY COMPLEX; OUTER ARM DYNEIN; PROTEOMIC ANALYSIS; SCHMIDTEA-MEDITERRANEA; SEQUENCE-ANALYSIS; MOTILE CILIA; FLAGELLAR; GENES; CHAIN; PROTEIN;

D O I：

10.1016/j.ajhg.2013.08.015

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Primary ciliary dyskinesia (PCD) is caused when defects of motile cilia lead to chronic airway infections, male infertility, and situs abnormalities. Multiple causative PCD mutations account for only 65% of cases, suggesting that many genes essential for cilia function remain to be discovered. By using zebrafish morpholino knockdown of PCD candidate genes as an in vivo screening platform, we identified c21orf59, ccdc65, and c15orf26 as critical for cilia motility. c21orf59 and c15orf26 knockdown in zebrafish and planaria blocked outer dynein arm assembly, and ccdc65 knockdown altered cilia beat pattern. Biochemical analysis in Chlamydomonas revealed that the C21orf59 ortholog FBB18 is a flagellar matrix protein that accumulates specifically when cilia motility is impaired. The Chlamydomonas ida6 mutant identifies CCDC65/FAP250 as an essential component of the nexin-dynein regulatory complex. Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families. Similar to findings in zebrafish and planaria, mutations in C21orf59 caused loss of both outer and inner dynein arm components. Our results characterize two genes associated with PCD-causing mutations and elucidate two distinct mechanisms critical for motile cilia function: dynein arm assembly for C21orf59 and assembly of the nexin-dynein regulatory complex for CCDC65.

引用

页码：672 / 686

页数：15

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