Caluianu, Maria; (2025) Understanding kidney disease in arthrogryposis-renal-dysfunctioncholestasis (ARC) syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

ARC (arthrogryposis-renal-dysfunction-cholestasis) syndrome is a rare, developmental, autosomal recessive, multisystem disorder affecting the kidneys. It is caused by mutations in the VPS33B or VIPAS39 genes, with VPS33B mutations causing 75% of cases. Renal ARC syndrome is typically characterised by proximal tubule dysfunction. ARC syndrome is currently incurable, with patients rarely surviving beyond their first year of life. This thesis aims to enhance the current understanding of the renal component of this disorder to inform future therapies. To achieve this, three approaches were taken. Firstly, VPS33B expression in developing human and mouse kidneys was characterised to identify important time points that may be key to ARC syndrome progression. Secondly, a Vps33b deletion was carried out in Osr1- positive cells in mice by crossing an Osr1-Cre line with a Vps33b-floxed line to knockout Vps33b in nephron progenitors. This mouse line was then characterised as a potential model of renal ARC syndrome. Finally, an in vitro study was conducted to establish a human VPS33BCRISPR- knockout proximal tubular cell line and a perfusable 3D in vitro proximal tubule device to model the proximal tubular dysfunction characteristic of ARC syndrome. Results demonstrated widespread VPS33B expression in human and mouse kidneys, with prominent localisation in mouse proximal tubules at E16.5. Osr1-specific Vps33b-knockout mice showed no differences in gross morphology, nephron structures, progenitor cells, total nephron numbers, and apically polarised proximal tubular marker or junctional marker expression compared to wild-type counterparts. However, a clear mechanobiological ‘peeling’ phenotype was observed in a VPS33B-knockout proximal tubular cell line. RNA-seq analysis alongside cell detachment and adhesion complex staining experiments suggested a cell-matrix attachment defect was likely responsible for this phenotype. This attachment defect may play a role in renal ARC syndrome development and progression. These findings provide the first insights into the cause of renal dysfunction in ARC syndrome.

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