Abstract
Arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apical–basolateral 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 genotype–phenotype 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 33:1656–1664, 2012. © 2012 Wiley Periodicals, Inc.
Highlights
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (MIM# 208085) is an autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B; MIM# 608552) and VPS33B interacting protein, apical– basolateral polarity regulator (VIPAR; MIM# 613401) [Cullinane et al, 2010; Gissen et al, 2004]
We summarize all published variants found in VPS33B and VIPAR to date in a Leiden Open-Source Variation Database (LOVD) for ARC and report 15 novel mutations in VPS33B and five in VIPAR
To identify whether VPS33B and/or VIPAR may interact with the mammalian homotypic protein sorting (HOPS) complex, we studied their colocalization with human VPS18 protein, which has a central role in HOPS subunit interactions [Ostrowicz et al, 2010; Plemel et al, 2011]
Summary
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (MIM# 208085) is an autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B; MIM# 608552) and VPS33B interacting protein, apical– basolateral polarity regulator (VIPAR; MIM# 613401) [Cullinane et al, 2010; Gissen et al, 2004]. VPS33B and VIPAR are homologues of yeast Vps and Vps, respectively In yeast, these proteins along with two other class C vps proteins (Vps and Vps18) make up the core of homotypic protein sorting (HOPS) and class C core vacuole/endosome tethering (CORVET) complexes responsible for the maturation and control of vesicular trafficking from early to late endosomes and vacuoles [Peplowska et al, 2007]. HOPS contains Vps and Vps, with Vps shown to directly interact with Ypt-7-GTP, a Rab orthologue [Brett et al, 2008], whereas CORVET contains Vps and Vps8 Intermediate complexes containing both CORVETand HOPS-specific subunits raise the possibility that these complexes may convert “on-the-fly” from one complex to another [Peplowska et al, 2007]. Whether there is a mammalian equivalent of the yeast CORVET complex is still unclear [Zlatic et al, 2011]
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