title: Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome.
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.
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Holly
authors: H
authors: Smith
authors: Romain
authors: R
authors: Galmes
authors: Ekaterina
authors: E
authors: Gogolina
authors: Anna
authors: A
authors: Straatman-Iwanowska
authors: Kim
authors: K
authors: Reay
authors: Blerida
authors: B
authors: Banushi
authors: Christopher K
authors: CK
authors: Bruce
authors: Andrew R
authors: AR
authors: Cullinane
authors: Rene
authors: R
authors: Romero
authors: Richard
authors: R
authors: Chang
authors: Oanez
authors: O
authors: Ackermann
authors: Clarisse
authors: C
authors: Baumann
authors: Hakan
authors: H
authors: Cangul
authors: Fatma
authors: F
authors: Cakmak Celik
authors: Canan
authors: C
authors: Aygun
authors: Richard
authors: R
authors: Coward
authors: Carlo
authors: C
authors: Dionisi-Vici
authors: Barbara
authors: B
authors: Sibbles
authors: Carol
authors: C
authors: Inward
authors: Chong Ae
authors: CA
authors: Kim
authors: Judith
authors: J
authors: Klumperman
authors: A S
authors: AS
authors: Knisely
authors: Steven P
authors: SP
authors: Watson
authors: Paul
authors: P
authors: Gissen
mesh_terms: D001176:Arthrogryposis / Q000175:diagnosis* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002675:Child, Preschool; D002779:Cholestasis / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D025202:Molecular Diagnostic Techniques; D021381:Protein Transport; D022821:RNA Splice Sites; D051437:Renal Insufficiency / Q000175:diagnosis* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D022821:RNA Splice Sites; C539711:VIPAS39 protein, human; C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins