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Human Molecular Genetics Advance Access originally published online on December 21, 2006
Human Molecular Genetics 2007 16(2):173-186; doi:10.1093/hmg/ddl459
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Meckel–Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation

Helen R. Dawe1,{dagger}, Ursula M. Smith2,{dagger}, Andrew R. Cullinane2, Dianne Gerrelli4, Phillip Cox5, Jose L. Badano6, Sarah Blair-Reid2,3, Nisha Sriram1, Nicholas Katsanis6, Tania Attie-Bitach7, Simon C. Afford3, Andrew J. Copp4, Deirdre A. Kelly8, Keith Gull1 and Colin A. Johnson2,*

1 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK, 2 Section of Medical and Molecular Genetics, Division of Reproductive and Child Health and 3 The Liver Research Laboratories, Institute of Biomedical Research, University of Birmingham Medical School, Vincent Drive, Edgbaston, Birmingham B15 2TT, UK, 4 Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK, 5 Department of Histopathology, Birmingham Women's Hospital, Metchley Park Road, Birmingham B15 2TG, UK, 6 McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA, 7 Département de Génétique et INSERM U-393, Hôpital Necker Enfants-Malades, 149 rue de Sèvres, Paris 75743, France and 8 Children's Liver Unit, Princess of Wales Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK

* To whom correspondence should be addressed. Fax: +44 1216272618; Email: c.a.johnson{at}bham.ac.uk

Received September 21, 2006; Accepted December 5, 2006

Meckel–Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterized by renal cystic dysplasia, central nervous system malformations (typically, posterior occipital encephalocele), and hepatic developmental defects. Two MKS genes, MKS1 and MKS3, have been identified recently. The present study describes the cellular, sub-cellular and functional characterization of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridization studies for MKS3 in early human embryos showed transcript localizations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominantly localized to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localized to basal bodies, while meckelin localized both to the primary cilium and to the plasma membrane in ciliated cell-lines and primary cells. Meckelin protein with the Q376P missense mutation was unable to localize at the cell membrane. siRNA-mediated reduction of Mks1 and Mks3 expression in a ciliated epithelial cell-line blocked centriole migration to the apical membrane and consequent formation of the primary cilium. Co-immunoprecipitation experiments show that wild-type meckelin and MKS1 interact and, in three-dimensional tissue culture assays, epithelial branching morphogenesis was severely impaired. These results suggest that MKS proteins mediate a fundamental developmental stage of ciliary formation and epithelial morphogenesis.

{dagger} The authors wish it to be known that, the first two authors should be regarded as joint First Authors.


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