1. Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome
- Author
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Clarisse Baumann, Canan Aygün, Oanez Ackermann, Holly Smith, Carol I. Inward, Chong Ae Kim, Judith Klumperman, Richard J M Coward, Richard Chang, Christopher K. Bruce, Romain Galmes, Steven P Watson, Barbara Sibbles, Carlo Dionisi-Vici, Paul Gissen, Andrew R. Cullinane, A.S. Knisely, Rene Romero, Blerida Banushi, Hakan Cangul, Fatma Cakmak Celik, Kim Reay, Anna Straatman-Iwanowska, Ekaterina Gogolina, and OMÜ
- Subjects
Male ,Models, Molecular ,Heterozygote ,Vesicular Transport Proteins ,VIPAR ,Biology ,Compound heterozygosity ,medicine.disease_cause ,recycling endosomes ,03 medical and health sciences ,0302 clinical medicine ,Renal tubular dysfunction ,ostopenia ,Genotype ,VPS33B ,Genetics ,medicine ,Humans ,Renal Insufficiency ,Genetic Association Studies ,Research Articles ,Genetics (clinical) ,030304 developmental biology ,Arthrogryposis ,0303 health sciences ,Mutation ,Cholestasis ,Arc (protein) ,Ichthyosis ,Heterozygote advantage ,Sequence Analysis, DNA ,medicine.disease ,Phenotype ,HOPS complex ,3. Good health ,Protein Transport ,HEK293 Cells ,Molecular Diagnostic Techniques ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,RNA Splice Sites ,Carrier Proteins ,cholestasis - Abstract
Banushi, Blerida/0000-0002-4314-8369; Dionisi-Vici, Carlo/0000-0002-0007-3379; Gissen, Paul/0000-0002-9712-6122; Coward, Richard/0000-0001-6183-2546; Kim, Chong/0000-0002-1754-1300; Galmes, Romain/0000-0001-5616-5937 WOS: 000310975900007 PubMed: 22753090 Arthrogryposisrenal dysfunctioncholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in vacuolar protein sorting 33 homologue B (VPS33B) and VPS33B interacting protein, apicalbasolateral 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 genotypephenotype 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 33:16561664, 2012. (c) 2012 Wiley Periodicals, Inc. Wellcome TrustWellcome Trust [WT095662MA]; Bold FP7 ITN project [238821]; VICI of the Netherlands Organization for Scientific Research [918.56.611]; British Heart FoundationBritish Heart Foundation [RG/09/007/27917]; Kidney Research UKKidney Research UK (KRUK) [RP22/2012]; Medical Research CouncilMedical Research Council UK (MRC) [G0501901, G9818340B]; Great Ormond Street Hospital Childrens Charity [ICH1034] Contract grant sponsors: H.S. is an MRC PhD fellow; P.G. is a Wellcome Trust Senior Research Fellow in Clinical Sciences (WT095662MA); P.G. and B.B. are supported by Bold FP7 ITN project-238821; R.G. and J.K. were supported by VICI grant 918.56.611 of the Netherlands Organization for Scientific Research awarded to J.K.
- Published
- 2012
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