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VPS33B, VIPAS39, and the Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 

VPS33B, VIPAS39, and the Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome
Chapter:
VPS33B, VIPAS39, and the Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome
Author(s):

Paul Gissen

DOI:
10.1093/med/9780199934522.003.0193
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date: 26 February 2021

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome (OMIM 208085 and 613404) is a severe multisystem autosomal recessive disorder first described in the 1970s, and to date, approximately 100 cases of ARC have been reported [Gissen et al., 2006, Smith et al., 2012, and references within]. Horslen et al., 1994 coined the eponym of ARC syndrome and reported that although the hepatic changes may show variability, the combination of clinical features is usually consistent. Subsequently a high prevalence of ichthyosis, abnormal platelet morphology, intracranial defects, and diarrhea was noted. Renal features comprise variable degree of tubular dysfunction, proteinuria and nephrogenic diabetes insipidus. All patients with ARC fail to thrive and Smith et al, 2012 reported 2 children older then 3 years of age surviving with good quality of life. Autozygosity mapping approach was used to map the first ARCS1 locus and identify mutations in VPS33B [Gissen et al., 2004]. Yeast two-hybrid search for VPS33B interactors identified C14ORF133, which was then confirmed as an interacting protein by co-immunoprecipitation and co-localisation experiments. Mutations in C14ORF133, renamed as VIPAS39, were found in patients with ARC phenotype without VPS33B mutations [Cullinane et al, 2010]. VPS33B and VIPAS39 encode VPS33B and VIPAR respectively which are homologous to yeast Vps33 and Vps16 that are integral parts of Homotypic Protein Sorting (HOPS) and class C core vacuole/endosome tethering (CORVET) complexes [Baldenhaar and Ungermann, 2013]. In mammalian cells VPS33B and VIPAR form a protein complex that interacts with RAB11A and is likely to be involved in the membrane trafficking events that determine accurate localization of apical membrane proteins [Cullinane et al., 2010, Smith at al., 2012, and Graham et al, 2013].

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