Investigating renal disease in Bardet-Biedl syndrome using induced pluripotent stem cells

Student thesis: Doctoral ThesisDoctor of Philosophy


Bardet-Biedl syndrome (BBS) is a ciliopathy comprising blindness, polydactyly, obesity, hypogonadism and renal defects. It is inherited in an autosomal recessive manner and is classified as a rare disease, affecting 1:100,000 in Europe. BBS is genetically and phenotypically variable, but kidney defects impact a large percentage of patients and it is not clear how mutations lead to disease. Induced pluripotent stem cells (iPSCs) coupled with renal differentiation technologies offer a novel platform to investigate genetic disease in vitro. To this end, patient iPSCs harbouring mutations in BBS1, BBS2 and BBS10 were obtained through the Human Induced Pluripotent Stem Cell Initiative (HipSci), along with numerous healthy lines. This PhD sought to characterize iPSC-derived renal cultures from BBS patients and healthy individuals. 
Using a high-content imaging approach of single progenitor cells, 14 phenotypic features encompassing proliferation, differentiation and cell morphology were measured across a panel of healthy and BBS lines. Overall, the in vitro profile was comparable across the cohorts implying BBS mutations do not impinge on these basic cellular processes in kidney progenitor models. To probe phenotypes in a more developmentally mature state, a multicellular 3D organoid system was employed, focussing on the more pathogenic BBS10 mutant lines. 
Three patient lines with different mutations in BBS10 were employed. The line with the most deleterious mutation failed to generate any 3D organoid structures, correlating with low BBS10 gene expression throughout differentiation. The other two patient lines showed near normal mRNA levels of BBS10 and could generate multiple kidney lineages within organoids. Prolonging the culture period however caused degeneration of the proximal tubule compartment, suggesting aberrant protein function. These data highlight the important role of BBS10 in kidney development and maintenance.
Date of Award1 Aug 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorFiona Watt (Supervisor) & Francesca Capon (Supervisor)

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