Molecular Characteristics
ARL6 is located at chromosome 3q11.2 and encodes for ADP-ribosylation factor-like-6 protein, a member of the Ras family of small GTP-binding proteins. The protein forms a stable protein complex with 7 BBS proteins and BBIP10 and localizes to the ciliary membrane. The complex binds brain lipid liposomes and polymerizes to function in the lateral transport of cargo proteins to ciliary membranes.
Mutations and pathophysiology
Zebrafish knockout models for ARL6 resulted in a BBS-like phenotype with delayed retrograde melanosome transport and defects of ciliated kupffer vesicles. Mutation of the Bbs3l isoform of ARL6 resulted in mislocalization of the green cone opsen and impaired visual function. Bbs3l mouse knockout models showed disrupted photoreceptor inner segment architecture.
Pathogenic autosomal recessive ARL6 variants in humans have been shown to lead to either syndromic (BBS3) or nonsyndromic (RP55) retinitis pigmentosa.
Aldahmesh et al. 2009 reported the homozygous variant (c.619C>T; p.A89V) in ARL6 (NM_032146.3) resulting in nonsyndromic retinitis pigmentosa (RP55) in 4 siblings from a consanguineous Saudi Arabian family.
Safieh et al. 2010 reported 3 homozygous variants in ARL6 (NM_032146.3):
1) c.266C>T; p.A89V in 4 individuals from a consanguineous family with RP55
2) c.431C>T; p.S144F in 4 individuals from another consanguineous family with BBS3
3) c.732+1952_899-3806-del4139; p.C160X in 4 individuals from another consanguineous family with BBS3
Notably, the clinical findings were variable between families but highly consistent within the families.
Pretorius et al. 2011 reported a functional characterization of the ARL6 A89V missense mutation which resulted in nonsyndromic retinitis pigmentosa (RP55). Evaluation of the function of the ARL6 A89V variant was performed by analysing gene knockdown of bbs3 coupled with RNA rescue in zebrafish. The A89V mutation can suppress the melanosome transport defects, but not the vision impairment observed with the loss of bbs3. The fact that the A89V mutation can function in melanosome transport shows that the mutant form of the protein can still function in tissues that are generally impacted by BBS and uncovers an amino acid in BBS3 that, while dispensable in other cell types, is essential for the visual system.
ARL6