The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation
Authors: Dianne Gerrelli
Helen R Dawe
Keith Gull
Andrew J Copp
Nisha Sriram
Tania Attie-Bitach
Ursula M Smith
Phillip Cox
Sarah Blair-Reid
Nicholas Katsanis
Simon C Afford
Deirdre A Kelly
Jose L Badano
Andrew R Cullinane
Colin A Johnson
Journal: Human molecular genetics (2007)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Meckel-Gruber syndrome; MKS1; MKS3; renal cystic dysplasia; central nervous system malformations
Affiliations: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

Abstract:  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. 

Retracted: No

PubPeer comments:
 As a neuropathologist, I m interested in Meckel syndrome and the different proteins whose mutations are responsible for these genetic diseases. I found on figure 1 A and B ![file] The quality of preservation of this human embryo seems to be problematic. Are the authors sufficiently confident for using it for in situ hybridization? ![file] The authors stated thta this section is frontal. Due to the technical problems I pointed, I would be very interested to know the exact significance of the different structures (red, green and blue arrows). ![file] At last, according to the authors MI is supposed to be the ventral midline of the posterior forebrain. This is an error: the ventral midline is indicated by my red arrow. This should be corrected to avoid dissemination of confusion. , 
 Histological description is poor (#1) ![file] The authors indicate an expression of the gene in the floor of the rhombencephalon. The floor is the exact midline, this is the thinnest region of the neural tube. Such is not the case on this figure. The region of expression is the basal plate. See this figure modified from Mu00fcller and O Rahilly ![file] ,