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ARL6
ARF like GTPase 6
ARL6 is located on the long (q) arm of chromosome 3, at band 3q11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
ARL6 (ARF like GTPase 6) encodes a member of the ADP-ribosylation factor family of small GTPases. These proteins act as molecular switches, cycling between active and inactive states to regulate cellular processes. The ARL6 protein is integral to the assembly and maintenance of primary cilia, antenna-like projections on the cell surface that detect chemical and mechanical signals from the surrounding environment. Disruption of ARL6 function impairs ciliary structure and signalling, leading to a spectrum of developmental and metabolic abnormalities. The gene is catalogued on UK clinical diagnostic panels for ciliopathies, reflecting its relevance to inherited conditions affecting vision, kidney function, skeletal development, and metabolic regulation.
What the gene does
The ARL6 protein functions as a small GTPase that regulates protein trafficking to the primary cilium. In its GTP-bound active state, ARL6 recruits cargo proteins destined for the ciliary membrane, ensuring proper ciliary composition and signalling capacity. Primary cilia serve as cellular antennae, housing receptors for pathways including Hedgehog, Wnt, and receptor tyrosine kinase signalling. ARL6 specifically mediates the ciliary localisation of proteins involved in these pathways, thereby influencing developmental patterning, cellular differentiation, and metabolic homeostasis. The protein operates within the BBSome, a multi-subunit complex that transports membrane-associated proteins into and out of the cilium. Loss of ARL6 activity disrupts BBSome function, resulting in abnormal accumulation or depletion of signalling molecules at the ciliary membrane. This disruption affects tissues reliant on ciliary signalling, including photoreceptors in the retina, renal tubular epithelium, hypothalamic neurons regulating appetite, and limb bud mesenchyme during embryonic development.
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Chromosome location
ARL6 is located on chromosome 3 at cytogenetic band 3q11.2. The genomic region spans multiple exons encoding a relatively compact open reading frame. The chromosomal position places ARL6 within a gene-dense region of the long arm of chromosome 3, although the gene itself is not part of a recognised gene cluster.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The ARL6 protein consists of 186 amino acids and belongs to the ADP-ribosylation factor superfamily, sharing structural features common to small GTPases including nucleotide-binding motifs and switch regions that undergo conformational changes upon GTP hydrolysis. These conserved elements enable the protein to alternate between active and inactive states, a property essential for its regulatory function.
Key variants
Pathogenic variants in ARL6 are inherited in an autosomal recessive pattern, meaning affected individuals typically carry variants on both gene copies. Loss-of-function changes, including nonsense, frameshift, and splice-site variants, are commonly reported. Missense variants affecting the GTP-binding pocket or switch regions can also impair protein function. The variant spectrum reflects diverse molecular consequences that converge on disrupted ciliary trafficking.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.185+1G>C | - | Pathogenic | ★★☆☆ | ARL6-related disorder |
c.228C>G | p.Tyr76Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 55 |
c.255-2A>T | - | Pathogenic | ★★☆☆ | Retinitis pigmentosa 55 |
c.272T>C | p.Ile91Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome |
c.281T>C | p.Ile94Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome 1 |
c.350-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 55 |
c.4G>T | p.Gly2Ter | Pathogenic | ★★☆☆ | Bardet-Biedl syndrome 1 |
c.534A>G | p.Gln178= | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome 3 |
c.92C>G | p.Thr31Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Bardet-Biedl syndrome 3 |
c.92C>T | p.Thr31Met | Pathogenic | ★★☆☆ | Retinitis pigmentosa 55 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in ARL6 cause Bardet-Biedl syndrome, a ciliopathy characterised by retinal dystrophy leading to progressive vision loss, obesity with early onset in childhood, polydactyly or other limb malformations, renal structural abnormalities, hypogonadism, and cognitive impairment. The syndrome exhibits clinical variability, with some individuals presenting a subset of cardinal features. Ciliary dysfunction underlies the multi-system nature of the condition, as primary cilia are present on many cell types and mediate diverse signalling events during development and adult tissue homeostasis. The severity and combination of features can vary between individuals, even within the same family, reflecting genetic background and modifier effects.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ARL6 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
ARL6 holds green classification status on multiple NHS Genomic Medicine Service gene panels, indicating strong evidence for clinical validity. Relevant panels include Bardet-Biedl syndrome, retinal disorders, renal ciliopathies, ophthalmological ciliopathies, rare multisystem ciliopathy disorders, skeletal dysplasia, severe early-onset obesity, foetal anomalies, intellectual disability, and limb disorders. The gene is also listed on the Developmental Disorders Genotype-to-Phenotype (DDG2P) database. This breadth of panel membership reflects the multi-organ impact of ARL6-related ciliopathies and supports its inclusion in genomic testing pathways for individuals with relevant clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of ARL6 in the cell?
ARL6 encodes a small GTPase that regulates the transport of proteins to and from the primary cilium, a sensory organelle on the cell surface. The protein functions within the BBSome complex, ensuring proper ciliary composition and enabling signalling pathways essential for development and tissue function.
How is ARL6-related Bardet-Biedl syndrome inherited?
The condition follows an autosomal recessive inheritance pattern. An affected individual typically has pathogenic variants on both copies of ARL6, one inherited from each parent. Parents who each carry one variant are usually unaffected but have a 25% chance with each pregnancy of having an affected child.
Is ARL6 included on NHS genetic testing panels?
Yes, ARL6 is included on multiple NHS Genomic Medicine Service panels with green status, including those for Bardet-Biedl syndrome, retinal disorders, renal ciliopathies, skeletal dysplasia, and severe early-onset obesity, among others. This reflects robust evidence supporting its clinical utility in diagnostic testing.