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]
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).
[ARTHROGRYPOSIS, RENAL DYSFUNCTION, AND CHOLESTASIS 1; ARCS1](https://omim.org/entry/208085)
[VPS33B LATE ENDOSOME AND LYSOSOME ASSOCIATED; VPS33B](https://omim.org/entry/608552)
Arthrogryposis, renal dysfunction, and cholestasis-1 (ARCS1) is caused by homozygous or compound heterozygous mutation in the VPS33B gene. [from MIM:208085, 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]
Clinical features of ARCS are consistent with abnormal intracellular protein trafficking and defective membrane fusion mechanisms in various tissues. [from MIM:608552, 2017.11.29]
One to one (1 human to 1 Drosophila).
Moderate-scoring ortholog of human VPS33B (1 Drosophila to 1 human); Dmel\Vps33B shares 22% identity and 45% similarity with the human gene.
