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Human Molecular Genetics Advance Access published online on December 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl459
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© The Author 2006. Published by Oxford University Press. All rights reserved

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

Helen R. Dawe1,9, Ursula M. Smith2,9, Andrew R. Cullinane2, Dianne Gerrelli3, Phillip Cox4, Jose L. Badano5, Sarah Blair-Reid2,6, Nisha Sriram1, Nicholas Katsanis5, Tania Attie-Bitach7, Simon C. Afford6, Andrew J. Copp3, 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, University of Birmingham Medical School, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK 3 Neural Development Unit, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK 4 Dept. of Histopathology, Birmingham Women's Hospital, Metchley Park Road, Birmingham B15 2TG, UK 5 McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore MD 21205, USA 6 The Liver Research Laboratories, Institute of Biomedical Research, University of Birmingham Medical School, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK 7 Département de Génétique et INSERM U-393, Hôpital Necker Enfants-Malades, 149 rue de Sèvres, Paris 75743, France 8 Children's Liver Unit, Princess of Wales Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK

* E-MAIL c.a.johnson{at}bham.ac.uk; FAX 0044 (121) 627 2618

Received September 21, 2006; Revised December 5, 2006; Accepted December 5, 2006

Meckel-Gruber syndrome (MKS) is an autosomal recessive lethal malformation syndrome characterised 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 characterisation of the novel proteins, MKS1 and meckelin, encoded by these genes. In situ hybridisation studies for MKS3 in early human embryos showed transcript localisations in agreement with the tissue phenotype of MKS patients. Both MKS proteins predominately localised to epithelial cells, including proximal renal tubules and biliary epithelial cells. MKS1 localised to basal bodies, while meckelin localised 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 localise 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.

9 These authors contributed equally to this work


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