Disease relevance of ARL6

• Using a bioinformatic screen for ciliary genes in combination with mutational analyses, we identified ARL6 as the gene underlying Bardet-Biedl syndrome type 3, a multisystemic disorder characterized by obesity, blindness, polydactyly, renal abnormalities and cognitive impairment [1].
• Mutations in a related human family member, Arl6, result in Bardet-Biedl syndrome in humans, which is characterized by genital, renal, and retinal abnormalities, obesity, and learning deficits [2].
• However, the "BBS3 phenotype," which includes polydactyly of all four limbs and a progression to morbid obesity, was not observed [3].
• NF-kappaB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis [4].
• We then infected ARL-6 cells with recombinant adenovirus containing mutant (non-degradable) IkBa (Adv-mIkappaBalpha), and examined whether this rendered ARL-6 cells more sensitive to oxidative stress-induced apoptosis [4].

High impact information on ARL6

• We uncovered four different homozygous substitutions in ARL6 in four unrelated families affected with Bardet-Biedl syndrome, two of which disrupt a threonine residue important for GTP binding and function of several related small GTP-binding proteins [1].
• We hypothesized that the genomes of model organisms that contained the orthologues to known BBS genes would also likely contain a BBS3 orthologue [5].
• BBS3 was previously mapped to chromosome 3 by linkage analysis in a large Israeli Bedouin kindred [5].
• By including multiple organisms that have relatively small genome sizes in the analysis, the number of candidate genes was reduced, and a few genes mapping to the BBS3 interval emerged as the best candidates for this disorder [5].
• Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet-Biedl syndrome (BBS3) [5].

Biological context of ARL6

• Haplotype analysis reduces the BBS3 critical region to a 6-cM interval between D3S1595-D3S1753 [3].
• Linkage analysis with microsatellite markers showed that the disease in the family was assigned to a region around marker loci at 3p13-p12 (maximum LOD score = 4.15 and recombination fraction straight theta = 0, at D3S1603 microsatellite marker), to which the BBS3 locus has been mapped [6].
• Conversely, NF-kappaB inhibition sensitises ARL-6 cells to H2O2-induced apoptosis [4].
• Adv-mIkappaBalpha sensitized ARL-6 cells to H2O2-induced apoptosis, but cell proliferation was minimally suppressed [4].

Anatomical context of ARL6

• We report here the isolation of a new member of the ADP-ribosylation factor (ARF)-like family (ARL-6) present in the J2E erythroleukemic cell line, but not its myeloid variants [7].
• Co-immunoprecipitation of ARL-6 confirmed a stable association between ARL-6 and SEC61beta in COS cells [7].
• METHODS: Cultured primary rat hepatocytes and ARL-6 cells were treated with graded doses of H2O2 [4].

Analytical, diagnostic and therapeutic context of ARL6

• We studied the three original families used for the identification of BBS2, BBS3, and BBS4 loci to define the ocular phenotypes of patients (n = 34) and obligate carriers (n = 32) using clinical examination and electroretinography (ERG) [8].

References