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Banushi, Blerida/0000-0002-4314-8369; Dionisi-Vici, Carlo/0000-0002-0007-3379; Gissen, Paul/0000-0002-9712-6122; Coward, Richard/0000-0001-6183-2546; Kim, Chong/0000-0002-1754-1300; Galmes, Romain/0000-0001-5616-5937 WOS: 000310975900007 PubMed: 22753090 Arthrogryposisrenal dysfunctioncholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apicalbasolateral polarity regulator (VIPAR). Cardinal features of ARC include congenital joint contractures, renal tubular dysfunction, cholestasis, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients with ARC do not survive past the first year of life. We report two patients presenting with a mild ARC phenotype, now 5.5 and 3.5 years old. Both patients were compound heterozygotes with the novel VPS33B donor splice-site mutation c.1225+5G>C in common. Immunoblotting and complementary DNA analysis suggest expression of a shorter VPS33B transcript, and cell-based assays show that c.1225+5G>C VPS33B mutant retains some ability to interact with VIPAR (and thus partial wild-type function). This study provides the first evidence of genotypephenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype. We have established an interactive online database for ARC (https://grenada.lumc.nl/LOVD2/ARC) comprising all known variants in VPS33B and VIPAR. Also included in the database are 15 novel pathogenic variants in VPS33B and five in VIPAR. Hum Mutat 33:16561664, 2012. (c) 2012 Wiley Periodicals, Inc. Wellcome TrustWellcome Trust [WT095662MA]; Bold FP7 ITN project [238821]; VICI of the Netherlands Organization for Scientific Research [918.56.611]; British Heart FoundationBritish Heart Foundation [RG/09/007/27917]; Kidney Research UKKidney Research UK (KRUK) [RP22/2012]; Medical Research CouncilMedical Research Council UK (MRC) [G0501901, G9818340B]; Great Ormond Street Hospital Childrens Charity [ICH1034] Contract grant sponsors: H.S. is an MRC PhD fellow; P.G. is a Wellcome Trust Senior Research Fellow in Clinical Sciences (WT095662MA); P.G. and B.B. are supported by Bold FP7 ITN project-238821; R.G. and J.K. were supported by VICI grant 918.56.611 of the Netherlands Organization for Scientific Research awarded to J.K.

Background. Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a multisystem autosomal-recessive disorder caused by defects in the VPS33B and VIPAR genes, involved in localization of apical membrane proteins. Affected children usually die by 1 year of age, often secondary to infective complications. The classic renal manifestation previously described in ARC syndrome is proximal–tubular dysfunction. The aim of this study is to gain further insight into the renal manifestations of this syndrome. Methods. Clinical review of three cases of ARC syndrome presenting to a tertiary centre. Together with measurement of VPS33B and VIPAR protein expression in the human glomerulus. Results. The cases demonstrated severe failure to thrive and in addition to commonly described features profound proteinuria and albuminuria, together with hypoalbuminaemia, suggesting glomerular involvement of this syndrome. Western blotting of conditionally immortalized human glomerular cells and ex vivo immunofluorescent analysis of the human glomerulus revealed that VPS33B and VIPAR were highly expressed in glomerular endothelium, and podocytes, but not in the mesangium. Conclusions. ARC syndrome affects the glomerulus as well as the proximal tubule in the kidney. Our molecular studies suggest that both cell types that constitute the glomerular filtration barrier are affected in this condition, providing an explanation for the albuminuria that we have observed in our cases.