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General Information
Name
arthrogryposis, renal dysfunction, and cholestasis 1
FlyBase ID
FBhh0000669
Overview

This report describes arthrogryposis, renal dysfunction, and cholestasis 1 (ARCS1), which is a subtype of ARC syndrome; ARCS1 exhibits autosomal recessive inheritance. The human gene implicated in this disease is VPS33B, a protein involved in trafficking and sorting of lysosomal proteins. There is a single moderate-scoring fly ortholog, Vps33B, for which an amorphic allele and RNAi targeting constructs have been generated.

The human VPS33B gene has not been introduced into flies.

Animals homozygous for an amorphic mutation of Dmel\Vps33B are viable and fertile, but phagosomal maturation and function is impaired. Vps33B mutant flies exhibit extreme sensitivity to infections with non-pathogenic E. coli; the cause of death does not appear to be the bacterial load itself, but exaggerated anti-microbial responses to non-pathogenic microbes. This response mimics the recurrent sepsis that can contribute to death in ARC patients. Physical interactions of Dmel\Vps33B have been described; see below and in the Vps33B gene report.

[updated Nov. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: ARC syndrome
Symptoms and phenotype
ARC syndrome is a life-threatening autosomal recessive multisystem disorder. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive (Zhou and Zhang, 2014; pubmed:25239142).
See review by Zhou and Zhang, 2014 (pubmed:25239142).
Specific Disease Summary: arthrogryposis, renal dysfunction, and cholestasis 1
OMIM report
[ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 1; ARCS1](https://omim.org/entry/208085)
Human gene(s) implicated
[VACUOLAR PROTEIN SORTING 33, YEAST, HOMOLOG OF, B; VPS33B](https://omim.org/entry/608552)
Symptoms and phenotype
Genetics
Arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1) is caused by homozygous or compound heterozygous mutation in the VPS33B gene. [from OMIM:208085, 2017.11.29]
Cellular phenotype and pathology
Molecular information
Clinical features of ARCS are consistent with abnormal intracellular protein trafficking and defective membrane fusion mechanisms in various tissues. [from OMIM:608552, 2017.11.29]
VPS33B is a member of the Sec1-domain family of proteins, which interact with soluble NSF attachment protein receptors (SNAREs). SNAREs are involved in a variety of processes, including vesicular exocytosis, synaptic transmission, and general secretion, by facilitating vesicle targeting and fusion (Zhou and Zhang, 2014; pubmed:25239142).
May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes; mediates phagolysosomal fusion in macrophages. [Gene Cards, VSP33B; 2017.11.29]
Disease synonyms
ARCS1
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)
    One to one (1 human to 1 Drosophila).
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      Vacuolar protein sorting 33B (Vps33B) encodes a member of the family of SM proteins, which in conjunction with SNARE proteins catalyze membrane fusion events. The product of Vps33B, together with its binding partner encoded by Vps16B, forms a complex that is necessary for fusions between phagosomes and lysosomes. [Date last reviewed: 2018-11-08]
      Molecular function (GO)
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)
      Moderate-scoring ortholog of human VPS33B (1 Drosophila to 1 human); Dmel\Vps33B shares 22% identity and 45% similarity with the human gene.
      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (3 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti bait coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Interaction
      References
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      P-element activity
      References (5)