Colin A. Johnson

Molecular genetics of ciliopathies

In recent years, an ever-increasing number of inherited diseases, of previously unknown aetiology, have been shown to be 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.

In August 2005, my group in Birmingham identified mutations in the first gene, MKS3, for a severe autosomal recessive malformation syndrome, Meckel-Grüber syndrome (MKS), that is characterized by renal cystic dysplasia and central nervous system malformations. There is compelling evidence that MKS is a ciliopathy, and, following my move to Leeds in 2006, we are aiming to understand the molecular pathogenesis of this disorder, and other ciliopathies such as Joubert syndrome (JBTS) and Jeune syndrome, that have additional urological 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.

Dawe HR, Smith UM, Cullinane AR, Gerrelli D, Cox P, Badano JL, Blair-Reid S, Sriram N, Katsanis N, Attie-Bitach T, Afford SC, Copp AJ, Kelly DA, Gull K, Johnson CA. (2006) The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 16:173-86.

Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH 2nd, Harris PC, Johnson CA (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 38:191-6.

Johnson CA et al. (2003) Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet 40: 311-319.