期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 93, 期 5, 页码 932-944出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.10.003
关键词
-
资金
- Wellcome Trust [WT091310]
- Dutch Kidney Foundation [CP11.18, IP11.58]
- European Community [241955]
- Netherlands Organization for Scientific Research NWO [Veni-91613008]
- NIHR (Moorfields Eye Hospital BRC)
- British Heart Foundation
- UQ International PhD Scholarship
- University of Queensland postgraduate scholarship
- NHMRC
- Action Medical Research UK [RTF-1411]
- Newlife Foundation for Disabled Children
- Action Medical Research [1794, 2101] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1299] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10268, NF-SI-0507-10204] Funding Source: researchfish
Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据