The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans

被引：150

作者：

Wirschell, Maureen ^{[1
]}

Olbrich, Heike ^{[2
]}

Werner, Claudius ^{[2
]}

Tritschler, Douglas ^{[3
]}

Bower, Raqual ^{[3
]}

Sale, Winfield S. ^{[1
]}

Loges, Niki T. ^{[2
]}

Pennekamp, Petra ^{[2
]}

Lindberg, Sven ^{[4
,5
]}

Stenram, Unne ^{[6
,7
]}

Carlen, Birgitta ^{[6
,7
]}

Horak, Elisabeth ^{[8
]}

Koehler, Gabriele ^{[9
]}

Nuernberg, Peter ^{[10
,11
,12
]}

Nuernberg, Gudrun ^{[10
,11
,12
]}

Porter, Mary E. ^{[3
]}

Omran, Heymut ^{[2
]}

机构：

[1] Emory Univ, Sch Med, Dept Cell Biol, Atlanta, GA USA

[2] Univ Hosp Muenster, Dept Pediat, Munster, Germany

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

[4] Lund Univ, Dept Otorhinolaryngol Head & Neck Surg, Lund, Sweden

[5] Skane Univ Hosp SUS, Lund, Sweden

[6] Lund Univ, Dept Pathol, Lund, Sweden

[7] SUS, Lund, Sweden

[8] Med Univ Innsbruck, Div Cardiol & Pulmonol, Dept Pediat & Adolescents, A-6020 Innsbruck, Austria

[9] Univ Hosp Muenster, Inst Pathol, Munster, Germany

[10] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[11] Univ Cologne, CMMC, D-50931 Cologne, Germany

[12] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany

来源：

NATURE GENETICS | 2013年 / 45卷 / 03期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

CHLAMYDOMONAS-FLAGELLA; RADIAL SPOKES; DYSKINESIA; INNER; ARMS; MUTATIONS; IDENTIFICATION; ASYMMETRY; DEFECTS; MUTANTS;

D O I：

10.1038/ng.2533

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1, CCDC164, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in Chlamydomonas reinhardtii and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease.

引用

页码：262 / 268

页数：7

共 31 条

[1] The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation [J].

Becker-Heck, Anita ;

Zohn, Irene E. ;

Okabe, Noriko ;

Pollock, Andrew ;

Lenhart, Kari Baker ;

Sullivan-Brown, Jessica ;

McSheene, Jason ;

Loges, Niki T. ;

Olbrich, Heike ;

Haeffner, Karsten ;

Fliegauf, Manfred ;

Horvath, Judith ;

Reinhardt, Richard ;

Nielsen, Kim G. ;

Marthin, June K. ;

Baktai, Gyorgy ;

Anderson, Kathryn V. ;

Geisler, Robert ;

Niswander, Lee ;

Omran, Heymut ;

Burdine, Rebecca D. .

NATURE GENETICS, 2011, 43 (01) :79-U105

[2] Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia [J].

Blanchon, Sylvain ;

Legendre, Marie ;

Copin, Bruno ;

Duquesnoy, Philippe ;

Montantin, Guy ;

Kott, Esther ;

Dastot, Florence ;

Jeanson, Ludovic ;

Cachanado, Marine ;

Rousseau, Alexandra ;

Papon, Jean Francois ;

Beydon, Nicole ;

Brouard, Jacques ;

Crestani, Bruno ;

Deschildre, Antoine ;

Desir, Julie ;

Dollfus, Helene ;

Leheup, Bruno ;

Tamalet, Aline ;

Thumerelle, Caroline ;

Vojtek, Anne-Marie ;

Escalier, Denise ;

Coste, Andre ;

de Blic, Jacques ;

Clement, Annick ;

Escudier, Estelle ;

Amselem, Serge .

JOURNAL OF MEDICAL GENETICS, 2012, 49 (06) :410-416

[3] BENDING PATTERNS OF CHLAMYDOMONAS FLAGELLA .4. MUTANTS WITH DEFECTS IN INNER AND OUTER DYNEIN ARMS INDICATE DIFFERENCES IN DYNEIN ARM FUNCTION [J].

BROKAW, CJ ;

KAMIYA, R .

CELL MOTILITY AND THE CYTOSKELETON, 1987, 8 (01) :68-75

[4] Polarity and asymmetry in the arrangement of dynein and related structures in the Chlamydomonas axoneme [J].

Bui, Khanh Huy ;

Yagi, Toshiki ;

Yamamoto, Ryosuke ;

Kamiya, Ritsu ;

Ishikawa, Takashi .

JOURNAL OF CELL BIOLOGY, 2012, 198 (05) :913-925

[5] Molecular architecture of inner dynein arms in situ in Chlamydomonas reinhardtii flagella [J].

Bui, Khanh Huy ;

Sakakibara, Hitoshi ;

Movassagh, Tandis ;

Oiwa, Kazuhiro ;

Ishikawa, Takashi .

JOURNAL OF CELL BIOLOGY, 2008, 183 (05) :923-932

[6] Absence of nexin links as a possible cause of primary ciliary dyskinesia [J].

Carlén, B ;

Lindberg, S ;

Stenram, U .

ULTRASTRUCTURAL PATHOLOGY, 2003, 27 (02) :123-126

[7] The dynein regulatory complex is required for ciliary motility and otolith biogenesis in the inner ear [J].

Colantonio, Jessica R. ;

Vermot, Julien ;

Wu, David ;

Langenbacher, Adam D. ;

Fraser, Scott ;

Chen, Jau-Nian ;

Hill, Kent L. .

NATURE, 2009, 457 (7226) :205-U102

[8] The CSC is required for complete radial spoke assembly and wild-type ciliary motility [J].

Dymek, Erin E. ;

Heuser, Thomas ;

Nicastro, Daniela ;

Smith, Elizabeth F. .

MOLECULAR BIOLOGY OF THE CELL, 2011, 22 (14) :2520-2531

[9] Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia [J].

Fliegauf, M ;

Olbrich, H ;

Horvath, J ;

Wildhaber, JH ;

Zariwala, MA ;

Kennedy, M ;

Knowles, MR ;

Omran, H .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2005, 171 (12) :1343-1349

[10] Mechanisms of disease - When cilia go bad: cilia defects and ciliopathies [J].

Fliegauf, Manfred ;

Benzing, Thomas ;

Omran, Heymut .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (11) :880-893

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