Glomerular involvement in the arthrogryposis, renal dysfunction and cholestasis syndrome

Area of Science:

• Genetics
• Nephrology
• Pediatrics

Background:

• Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare, fatal genetic disorder.
• Caused by mutations in VPS33B and VIPAR genes, affecting protein localization.
• Previously, only proximal-tubular dysfunction was recognized as a renal manifestation.

Purpose of the Study:

• To investigate the full spectrum of renal manifestations in ARC syndrome.
• To explore the role of VPS33B and VIPAR in glomerular pathology.

Main Methods:

• Clinical review of three ARC syndrome cases.
• Analysis of VPS33B and VIPAR protein expression in human glomeruli.
• Western blotting and immunofluorescence of glomerular cells.

Main Results:

• Cases presented with severe failure to thrive, proteinuria, albuminuria, and hypoalbuminemia.
• VPS33B and VIPAR are highly expressed in glomerular endothelium and podocytes.
• Absence of VPS33B and VIPAR expression in the glomerular mesangium.

Conclusions:

• ARC syndrome impacts both the glomerulus and proximal tubules.
• VPS33B and VIPAR gene defects affect key cells of the glomerular filtration barrier.
• This provides a molecular explanation for observed albuminuria in ARC syndrome.