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.

Cholestasis, HOPS complex, Ostopenia, Recycling endosomes, VIPAR, VPS33B
dx.doi.org/10.1002/humu.22155, hdl.handle.net/1765/67760
Human Mutation
Department of Pediatrics

Smith, H, Galmes, R, Gogolina, E, Straatman-Iwanowska, A, Reay, E, Banushi, B, … Gissen, P. (2012). Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome. Human Mutation, 33(12), 1656–1664. doi:10.1002/humu.22155