Human Molecular Genetics Advance Access originally published online on June 10, 2009
Human Molecular Genetics 2009 18(17):3311-3323; doi:10.1093/hmg/ddp272
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Ciliary and centrosomal defects associated with mutation and depletion of the Meckel syndrome genes MKS1 and MKS3
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1 Department of Biochemistry / Molecular Biology 2 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA 3 Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA 4 Department of Medicine, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed at: Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: +1 5072660541; Fax: +1 5072669315.; Email: harris.peter{at}mayo.edu
Received March 30, 2009; Revised May 22, 2009; Accepted June 5, 2009
Meckel syndrome (MKS) is a lethal disorder characterized by renal cystic dysplasia, encephalocele, polydactyly and biliary dysgenesis. It is highly genetically heterogeneous with nine different genes implicated in this disorder. MKS is thought to be a ciliopathy because of the range of phenotypes and localization of some of the implicated proteins. However, limited data are available about the phenotypes associated with MKS1 and MKS3, and the published ciliary data are conflicting. Analysis of the wpk rat model of MKS3 revealed functional defects of the connecting cilium in the eye that resulted in lack of formation of the outer segment, whereas infertile wpk males developed spermatids with very short flagella that did not extend beyond the cell body. In wpk renal collecting duct cysts, cilia were generally longer than normal, with additional evidence of cells with multiple primary cilia and centrosome over-duplication. Kidney tissue and cells from MKS1 and MKS3 patients showed defects in centrosome and cilia number, including multi-ciliated respiratory-like epithelia, and longer cilia. Stable shRNA knockdown of Mks1 and Mks3 in IMCD3 cells induced multi-ciliated and multi-centrosomal phenotypes. These studies demonstrate that MKS1 and MKS3 are ciliopathies, with new cilia-related eye and sperm phenotypes defined. MKS1 and MKS3 functions are required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
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  S. D. Weatherbee, L. A. Niswander, and K. V. Anderson A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling Hum. Mol. Genet., December 1, 2009; 18(23): 4565 - 4575. [Abstract] [Full Text] [PDF]
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