ARL6 – Bardet-Biedl syndrome 3

The small GTPase ARL6 is part of the Ras superfamily and is crucial for ciliary membrane trafficking. Bardet-Biedl syndrome type 3 (Bardet-Biedl syndrome 3) is an autosomal recessive pleiotropic disorder characterized by obesity, progressive retinal degeneration leading to blindness, polydactyly, renal anomalies and cognitive impairment.

The causal role of ARL6 in BBS3 was established in four unrelated families, each harboring homozygous ARL6 variants including the initiation codon mutation c.1A>G (p.Met1Val) (PMID:15314642). These probands presented with classic BBS features of obesity, blindness, polydactyly and cognitive deficits. All variants were confirmed by targeted sequencing and were absent in control cohorts. While segregation data beyond proband identification are limited, the recurrence of biallelic mutations in independent pedigrees supports pathogenicity.

Variants reported in BBS3 span missense (e.g. p.Thr31Arg, p.Thr31Met), frameshift (e.g. c.506del (p.Gly169fs)), and start-loss classes, underscoring allelic heterogeneity (PMID:15314642). No founder or recurrent alleles have been described, and no detailed prevalence data are available. The observed variant spectrum is consistent with a loss-of-function mechanism in an autosomal recessive context.

Biochemical analyses demonstrated that BBS-associated ARL6 missense mutations abolish GTP binding and trigger proteasomal degradation of the mutant proteins, indicating impaired stability and function (PMID:19236846). Structural studies localized ARL6 to a ring-like assembly at the ciliary gate and revealed that pathogenic variants disrupt nucleotide binding and ciliary signaling (PMID:20207729).

Cellular and in vivo functional assays revealed that ARL6 controls cilium length and abundance, and modulates Wnt signaling, with BBS mutations failing to support normal ciliary assembly (PMID:20207729). In zebrafish, ARL6 knockdown induces intracellular transport delays and visual impairment reversible by wild-type but not variant ARL6, confirming variant-specific pathogenic effects (PMID:21282186).

Together, genetic and experimental data establish ARL6 loss-of-function as the basis of BBS3, linking defective GTPase activity to ciliary transport failure and pleiotropic clinical features. Molecular testing for ARL6 variants informs diagnosis and genetic counseling, and functional assays provide a platform for variant interpretation and potential therapeutic targeting.

References

• Nature Genetics • 2004 • Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. PMID:15314642
• Biochemical and biophysical research communications • 2009 • Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome. PMID:19236846
• The Journal of Biological Chemistry • 2010 • Bardet-Biedl syndrome-associated small GTPase ARL6 (BBS3) functions at or near the ciliary gate and modulates Wnt signaling. PMID:20207729
• Human Molecular Genetics • 2011 • Functional analysis of BBS3 A89V that results in non-syndromic retinal degeneration. PMID:21282186

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