Dissecting the molecular basis of ciliopathies

Cilia are hair-like structures present on most vertebrate cell types. They are sensory hubs with a profound influence on cell proliferation, polarity and differentiation. Defects in cilia formation or function cause a range of developmental disorders categorized as ciliopathies. 

The ciliopathies are multisystem disorders involving all major organs including kidney, brain, eye, airways and limbs, thus emphasizing the important roles that the cilium has in the function of most tissues. Mutations in > 150 genes have been identified as the molecular cause for human ciliopathies, however, the majority of ciliopathy patients still remain genetically unexplained. 

In our project, we study a cohort of ciliopathy patients in which no clinically significant findings were detected on an analysis of diagnostic high throughput sequencing (HTS) data, which primarily focus on known disease genes. We analyze all human genes in HTS data and screen promising novel disease gene candidates identified in a ciliopathy patient cohort within our network of international collaborators. We further perform in vitro experiments and study animal models to reveal the effects of the novel mutations on cilia structure and function, and on downstream signal transduction pathways.

In this project, we have so far identified novel structural variants in a patient with Joubert syndrome (1), and we have identified and characterized novel ciliopathy genes (2, 3). 

National collaborators
Patient recruitment and clinical investigations: Prof. P. Strømme (Department of Pediatrics, OUS) and Prof. B. Paus, Dr. I-L. Mero and Dr. Y. Sejersted (AMG)
In vivo experiments: Prof. C.V. Esguerra (NCMM, UiO)
In vitro experiments: Prof. C.A.M. Progida (IBV, UiO) and Dr. S. Patzke (OUS, Radiumhospitalet)

International collaborators:
In vivo experiments and patient cohorts: Prof. N. Katsanis and Prof. E.E. Davis (Advanced Center for Translational and Genetic Medicine, Children’s Hospital of Chicago, USA), Prof. C. Bergmann (University of Freiburg, Germany), Prof. B. Isidor and Prof. S. Küry (Centre Hospitalier Universitaire de Nantes, France), Prof. V. Belengeanu (Victor Babes University of Medicine and Pharmacy of Timisoara, Romania)

Examples from this work:

  1. Sumathipala and Strømme et al. (2020). BMC Medical Genetics. 21:96. Doi: 10.1186/s12881-020-01024-y
  2. Cogné, Latypova, Senaratne, Martin et al. (2020). American Journal of Human Genetics, 106:893-904. Doi: 10.1016/j.ajhg.2020.04.005
  3. Epting, Senaratne, Ott, Holmgren et al. (2020). Human Mutation. Doi: 10.1002/humu.24127
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