Smith, H;
Banushi, B;
Bruce, CK;
Cangul, H;
Gogolina, E;
Straatman-Iwanowska, A;
Gissen, P;
... Watson, SP; + view all
(2012)
Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome.
Human Mutation
, 33
(12)
1656 - 1664.
10.1002/humu.22155.
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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. © 2012 Wiley Periodicals, Inc.
| Type: | Article |
|---|---|
| Title: | Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/humu.22155 |
| Publisher version: | http://dx.doi.org/10.1002/humu.22155 |
| Language: | English |
| Additional information: | © 2012 WILEY PERIODICALS, INC. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1368875 |
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