DYX1C1 is required for axonemal dynein assembly and ciliary motility

被引：206

作者：

Tarkar, Aarti ^{[1
]}

Loges, Niki T. ^{[2
]}

Slagle, Christopher E. ^{[3
]}

Francis, Richard ^{[4
]}

Dougherty, Gerard W. ^{[2
]}

Tamayo, Joel V. ^{[3
]}

Shook, Brett ^{[1
]}

Cantino, Marie ^{[1
]}

Schwartz, Daniel ^{[1
]}

Jahnke, Charlotte ^{[2
]}

Olbrich, Heike ^{[2
]}

Werner, Claudius ^{[2
]}

Raidt, Johanna ^{[2
]}

Pennekamp, Petra ^{[2
]}

Abouhamed, Marouan ^{[2
]}

Hjeij, Rim ^{[2
]}

Koehler, Gabriele ^{[5
]}

Griese, Matthias ^{[6
]}

Li, You ^{[4
]}

Lemke, Kristi ^{[4
]}

Klena, Nikolas ^{[4
]}

Liu, Xiaoqin ^{[4
]}

Gabriel, George ^{[4
]}

Tobita, Kimimasa ^{[4
]}

Jaspers, Martine ^{[7
]}

Morgan, Lucy C. ^{[8
]}

Shapiro, Adam J. ^{[9
]}

Letteboer, Stef J. F. ^{[10
,11
]}

Mans, Dorus A. ^{[10
,11
]}

Carson, Johnny L. ^{[9
]}

Leigh, Margaret W. ^{[9
]}

Wolf, Whitney E. ^{[12
]}

Chen, Serafine ^{[3
]}

Lucas, Jane S. ^{[13
,14
]}

Onoufriadis, Alexandros ^{[15
]}

Plagnol, Vincent ^{[16
]}

Schmidts, Miriam ^{[15
]}

Boldt, Karsten ^{[17
,18
]}

Roepman, Ronald ^{[10
,11
,19
]}

Zariwala, Maimoona A. ^{[20
]}

Lo, Cecilia W. ^{[4
]}

Mitchison, Hannah M. ^{[15
]}

Knowles, Michael R. ^{[12
]}

Burdine, Rebecca D. ^{[3
]}

LoTurco, Joseph J. ^{[1
]}

Omran, Heymut ^{[2
]}

机构：

[1] Univ Connecticut, Dept Physiol & Neurobiol, Storrs, CT 06269 USA

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

[3] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

[4] Univ Pittsburgh, Sch Med, Dept Dev Biol, Pittsburgh, PA USA

[5] Univ Hosp Munster, Dept Pathol, Munster, Germany

[6] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

[7] Univ Hosp Leuven, Dept Otorhinolaryngol, Louvain, Belgium

[8] Concord Hosp, Dept Resp Med, Concord, NSW, Australia

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

[10] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands

[11] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands

[12] UNC Sch Med, Dept Med, Chapel Hill, NC USA

[13] Univ Southampton, Natl Inst Hlth Res, Primary Ciliary Dyskinesia Ctr, Southampton Resp Biomed Res Unit, Southampton, Hants, England

[14] Univ Hosp Southampton Natl Hlth Serv NHS Fdn Trus, Southampton, Hants, England

[15] UCL, Inst Child Hlth, Mol Med Unit, London, England

[16] UCL, Genet Inst, London, England

[17] Univ Tubingen, Inst Ophthalm Res, Div Expt Ophthalmol, Tubingen, Germany

[18] Univ Tubingen, Med Proteome Ctr, Tubingen, Germany

[19] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 ED Nijmegen, Netherlands

[20] UNC Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 09期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

OF-FUNCTION MUTATIONS; NEURONAL MIGRATION; CANDIDATE GENE; SITUS-INVERSUS; DYSKINESIA; PROTEIN; DYSLEXIA; DEFECTS; ASSOCIATION; VARIANT;

D O I：

10.1038/ng.2707

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4).

引用

页码：995 / +

页数：13

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