Molecular genetics of ciliopathies
In recent years, an ever-increasing number of inherited diseases, of previously unknown aetiology, are caused by defects in primary cilia and basal bodies. The aim of my work is to gain novel insights into the molecular mechanisms of early embryogenesis and neurodevelopment, by elucidating the role of primary ciliary and basal body function with key pathways of development.
My group identified mutations in the first gene, MKS3, for a severe autosomal recessive malformation syndrome, called Meckel-Gruber syndrome (MKS) that is characterized by renal cystic dysplasia and central nervous system malformations. MKS is a ciliopathy, and we aim to understand the molecular pathogenesis of this disorder, and other ciliopathies such as Joubert syndrome (JBTS) and Jeune syndrome with neurological or ophthalmological features.
We are interested in identifying new genes for MKS and JBTS by using the strategy of autozygosity mapping, but we will also continue the functional characterization of meckelin, the protein encoded by the MKS3 gene. Meckelin is a transmembrane receptor, with some similarities to the Frizzled class of receptors. We are particularly interested in identifying the interacting partners and downstream targets of the intracellular domain, as well as the ligands of this novel receptor.
Figure 1 Pedigrees of two consanguineous families with Meckel-Gruber syndrome, with haplotypes on chromosome 8q22 shown as vertical bars. The disease-associated haplotype is shown in black.
Figure 2 Immunofluoresence staining pattern for cilia in red (highlighted by the arrow) and the basal body in green. The cell nuclei are stained blue.
Dawe et al. (2007) The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary ciliary formation. Hum. Mol. Genet. 16: 173-86
Smith and Consugar et al. (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38: 191-196.
Johnson et al. (2003) Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J. Med. Genet. 40: 311-319. 84