Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome

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.