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

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 conge...

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Published in:Human mutation 2012-12, Vol.33 (12), p.1656-1664
Main Authors: Smith, Holly, Galmes, Romain, Gogolina, Ekaterina, Straatman-Iwanowska, Anna, Reay, Kim, Banushi, Blerida, Bruce, Christopher K., Cullinane, Andrew R., Romero, Rene, Chang, Richard, Ackermann, Oanez, Baumann, Clarisse, Cangul, Hakan, Cakmak Celik, Fatma, Aygun, Canan, Coward, Richard, Dionisi-Vici, Carlo, Sibbles, Barbara, Inward, Carol, Ae Kim, Chong, Klumperman, Judith, Knisely, A. S., Watson, Steven P., Gissen, Paul
Format: Article
Language:English
Subjects:
Arthrogryposis - diagnosis
Arthrogryposis - genetics
Carrier Proteins - genetics
Child, Preschool
cholestasis
Cholestasis - diagnosis
Cholestasis - genetics
Female
Genetic Association Studies
HEK293 Cells
Heterozygote
HOPS complex
Humans
Male
Models, Molecular
Molecular Diagnostic Techniques
ostopenia
Protein Transport
recycling endosomes
Renal Insufficiency - diagnosis
Renal Insufficiency - genetics
RNA Splice Sites
Sequence Analysis, DNA
Vesicular Transport Proteins - genetics
VIPAR
VPS33B
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Summary: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.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22155