Cilia and Human Diseases: Insights from the OFD Type I Syndrome
Cilia are microtubule-based organelles protruding from the cell surface of almost all mammalian cells and exert diverse motility and sensory function within the cell. Work from different groups has revealed that cilia have crucial roles in cell signalling pathways and in maintaining cellular homeostasis. The link between pathological phenotypes and ciliary dysfunction in humans was proposed in the 1970s. However, only recently mutations in proteins that localize to the basal body and axoneme of primary cilia were causally related to human diseases. Collectively, these human syndromes are called “ciliopathies”, disorders defined by unique clinical criteria, but which present many overlapping phenotypes such as retinal degeneration, polydactyly, situs inversus, mental retardation and CNS malformations, encephalocele and cysts in the kidney, liver and pancreas. Thousands of proteins potentially involved in ciliary function have been identified. However, much remains to be determined on the biology and functions of this complex organelle of growing biomedical importance.
Our laboratory has been involved for the past few years in the study of the pathogenetic mechanisms underlying the Oral-facial-digital type I syndrome (OFD1), which we demonstrated to be ascribed to dysfunction of primary cilia. To gain further insight on the molecular mechanisms and pathogenesis of ciliopathies, our laboratory presently focuses on multidisciplinary approaches, which include:
- Systems biology approaches to perform a global analysis of ciliary gene expression. This analysis will allow the identification of specific gene regulatory networks underlying cilia functions
- Cell biology approaches to study the role of the cytoskeleton in basal body function and ciliogenesis in in vitro and in vivo models
- Functional studies to unravel the link between ciliary proteins and ubiquitin-dependent proteasomal degradation