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

Research output: Contribution to journalArticlepeer-review

Authors

  • Holly Smith
  • Romain Galmes
  • Ekaterina Gogolina
  • Kim Reay
  • Andrew R Cullinane
  • Rene Romero
  • Richard Chang
  • Oanez Ackermann
  • Clarisse Baumann
  • Fatma Cakmak Celik
  • Canan Aygun
  • Richard Coward
  • Carlo Dionisi-Vici
  • Barbara Sibbles
  • Carol Inward
  • Chong Ae Kim
  • Judith Klumperman
  • A S Knisely
  • Steve Watson

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)1656-64
Number of pages9
JournalHuman Mutation
Volume33
Issue number12
Publication statusPublished - 2012