This report describes arthrogryposis, renal dysfunction, and cholestasis 2 (ARCS2), which is a subtype of ARC syndrome; ARCS2 exhibits autosomal recessive inheritance. The human gene implicated in this disease is VIPAS39, which encodes VPS33B-interacting protein, apical-basolateral polarity regulator, spe-39 homolog, a protein involved in trafficking and sorting of lysosomal proteins. There is one high-scoring fly ortholog, Vps16B, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated.
VIPAS39 has not been transgenically expressed in flies.
Animals homozygous for an amorphic mutation of Dmel\Vps16B are viable and fertile, but they exhibit a defect in phagosome maturation, and as a consequence are sensitive to infections with normally non-pathogenic microbes. Hemocytes (fly macrophages) in homozygous animals engulf bacteria but fail to digest them. (The original designation of this gene was "fob", full-of-bacteria.) The Dmel\Vps16B protein is reported to physically interact with Dmel\Vps33B; see below and in the gene report for Vps16B.
[updated Jun. 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 2; ARCS2](https://omim.org/entry/613404)
[VPS33B-INTERACTING PROTEIN, APICAL-BASOLATERAL POLARITY REGULATOR, SPE39 HOMOLOG; VIPAS39](https://omim.org/entry/613401)
Arthrogryposis, renal dysfunction and cholestasis syndrome 2 (ARCS2) is a multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common. The disease is caused by mutations affecting the gene represented in this entry. In liver, CEACAM5 and ABCB11 are mislocalized and E-cadherin expression is decreased. [From UniProt, uniprot:Q9H9C1 2016.01.13]
Arthrogryposis, renal dysfunction, and cholestasis-2 (ARCS2) is caused by homozygous or compound heterozygous mutation in the VIPAS39 gene. [From MIM:613404, 2016.01.13]
Knockdown of vipas39 in zebrafish resulted in biliary excretion and E-cadherin (CDH1; MIM:192090) defects similar to those in individuals with ARC syndrome (see ARCS1, MIM:208085) caused by mutation in VPS33B (MIM:608552) or VIPAS39. Vipas39- and Vps33b-deficient mouse inner medullary collecting duct (mIMCD-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 (ortholog of human CEACAM5, MIM:114890) expression was due to missorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. Cullinane et al. (2010, pubmed:20190753) concluded that the VPS33B-VIPAS39 complex has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney. [From MIM:613401, 2016.01.14]
VIPAS39 is involved in intracellular sorting and trafficking of lysosomal proteins (Zhu et al., 2009, pubmed:19109425). Homotypic fusion and vacuole protein sorting (HOPS) complexes regulate intracellular vesicle docking through interaction with SNAREs (see MIM:604026). In HeLa and HEK293 cells, VIPAS39 has been shown to interact with a number of endogenous or cotransfected HOPS components, including VPS33A (MIM:610034) and VPS33B (MIM:608552), the gene associated with ARCS1 (MIM:208085). RNAi-knockdown of VIPAS39 in HEK293 cells affects the morphology and sorting of RAB11 (see MIM:605570)- and syntaxin-13 (STX13, or STX12, MIM:606892)-positive recycling endosomes and RAB7 (MIM:602298)-, syntaxin-7 (STX7; MIM:603217), and syntaxin-8 (STX8; MIM:604203)-positive late endosomes. It did not alter Golgi-to-sorting endosome traffic. VIPAS39 knockdown in HeLa cells perturbs M6PR (MIM:154540) trafficking and M6PR-mediated delivery of the lysosomal enzyme cathepsin D (CTSD; MIM:116840), and delays degradation of internalized EGFR (MIM:131550). These results indicate that VIPAS39 regulates the sorting and trafficking of lysosome resident proteins along the sorting and recycling pathways (Zhu et al., 2009, pubmed:19109425). [From MIM:613401, 2016.01.14]
One to one: 1 human to 1 Drosophila.
Ortholog of human VIPAS39 (1 Drosophila to 1 human).
Dmel\Vps16B shares 26% identity and 42% similarity with human VIPAS39.
