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  current news   Press   selected story    
     
  9 January 2015  
  Mutations in CCDC11,which encodes a coiled-coil containing ciliary protein, causes situs inversus due to dysmotility of monocilia in the left-right organizer
 
 




Authors
Vijayashankaranarayanan Narasimhan1,#, Rim Hjeij2,#, Shubha Vij1,7, Niki Tomas Loges2, Julia Wallmeier2, Cordula Koerner-Rettberg3, Claudius Werner2, Surin Kumar Thamilselvan1, Adrian Boey4, Semil Choksi1, Petra Pennekamp2, Sudipto Roy1,5,6,* and Heymut Omran2,*

1  Genes, Development and Disease Laboratory, Institute of Molecular and Cell Biology, Proteos, 61     Biopolis Drive, Singapore 138673
2  University Hospital Muenster, Department of Pediatrics, Albert Schweitzer Campus 1, Muenster 48149,     Germany
3  Klinik für Kinder-und Jugendmedizin im St. Josef-Hospital, Ruhr-Universität Bochum, Bochum,     Germany
4  Institute of Medical Biology – Institute of Molecular and Cell Biology Joint Electron Microscopy Suite,     B2-14 Matrix, 20 Biopolis Street, Singapore 138671
5  Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore     117543
6  Department of Pediatrics, National University of Singapore, 1E Kent Ridge Road, Singapore 119228,     Singapore
7  Present address: Temasek Life Sciences Laboratory, 1 Research Link, Singapore 117604

#  These authors contributed equally

Published online ahead of print in Human Mutation on 11 December 2014.

Abstract
In vertebrates, establishment of left-right (LR) asymmetry is dependent on cilia-driven fluid flow within the LR organizer. Mutations in CCDC11 disrupt LR asymmetry in humans, but how the gene functions in LR patterning is presently unknown. We describe a patient with situs inversus totalis carrying homozygous loss-of-function mutations in CCDC11. We show that CCDC11 is an axonemal protein in respiratory cilia, but is largely dispensable for their structure and motility. To investigate the role of CCDC11 in LR development, we studied the zebrafish homolog of the gene. Like in human respiratory cilia, loss of Ccdc11 causes minor defects in the motility of zebrafish kidney cilia, although the protein localizes to their axonemes and base. By contrast, Ccdc11 localizes exclusively to the basal bodies of cilia within Kupffer’s vesicle (KV), the organ of laterality of teleost fishes, and within the spinal canal. Moreover the rotational motion of the cilia in these tissues of ccdc11 deficient embryos was strongly impaired. Our findings demonstrate that CCDC11 has a conserved essential function in cilia of the vertebrate LR organizer. To the best of our knowledge, this is the first ciliary component which has a differential localization and function in different kinds of motile cilia.

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Figure:

Figure Legend:
(A) Pedigree of patient OP-1069-II1 (B) Patient OP-1069-II1 carries a homozygous point mutation (c.121C>T) in CCDC11, causing a premature stop codon. (C) A chest X-ray of patient OP-1069-II1, the left side marked with an ‘L’, showing situs inversus totalis. The heart is indicated with an arrowhead. (D) Localization of GFP-Ccdc11 to base of motile cilia in Kupffer’s vesicle (KV), the organ of laterality in the zebrafish embryo. (E) High resolution images of the localization of GFP-Ccdc11 to KV motile cilia. Scale bar = 5 μm

For more information on Sudipto ROY's laboratory, please click here.