ARL6

ARL6 stands for "ARF-like GTPase 6," and the gene is also called BBS3 and RP55. Its protein belongs to a family of small "switch" proteins that help regulate the movement of material inside cells. In the retina and other tissues, this protein works at the cilium Researchers first linked it to human disease when they found ARL6 changes in families with Bardet-Biedl syndrome, Type 3. Bardet-Biedl syndrome can affect the eyes, kidneys, hands and feet, weight, and learning. The gene also produces a longer, eye-specific version of the protein called BBS3L, which is made mostly in the eye and appears to have a specialized role in vision. Bardet-Biedl syndrome linked to ARL6 is inherited in an autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) pattern, which means a person typically has a disease-causing change in both copies of the gene.

The most consistent eye feature reported with ARL6 changes is a progressive breakdown of the retina's photoreceptors, the cells that sense light. Many people first notice trouble seeing in dim light or at night, along with reduced sharpness of vision. In a Saudi study of Bardet-Biedl syndrome, most patients had advanced retinal disease and were legally blind by early adulthood, and their retinal responses were often undetectable on electroretinography, a test of retinal electrical activity. The exact pattern varies between people. Different reports describe rod-cone dystrophy, cone-rod dystrophy, or a more generalized loss of both cell types. One case report described an unusual "rod-sparing" picture in a person with ARL6 changes, where the cone cells were affected more than the rods. An earlier study also found that nearsightedness (myopia) was associated with the BBS3/ARL6 form of the syndrome. Because the syndrome is highly variable even within the same family, age of onset and speed of vision change differ from person to person and cannot be predicted from the gene name alone.

It is well established that changes in both copies of ARL6 can cause Bardet-Biedl syndrome, a diagnosis first defined for this gene in 2004. Beyond the eyes, the syndrome commonly includes extra fingers or toes (polydactyly), obesity, kidney abnormalities, and learning or cognitive difficulties, though not every person has every feature. ARL6-related disease has been reported across many populations, including Saudi Arabian, Turkish, Pakistani, Indian, Japanese, Lebanese, and Mexican patients, often through gene-panel or exome sequencing. On the island of La Réunion, a single founder variant in ARL6/BBS3 accounts for a notably high local frequency of the syndrome, which shows how much its prevalence can depend on ancestry. Laboratory and animal studies help explain the biology. For example, the ARL6 protein normally helps a protein group called "BBSome" enter the cilium; mice lacking Bbs3 develop retinal degeneration along with other features of the syndrome. Studies in zebrafish and mice also showed that the eye-specific BBS3L version of the protein is needed for normal retinal function and organization.

There is no clear rule linking a specific ARL6 change to a specific outcome, and studies repeatedly note wide variation between and even within families. Why the retina is affected differently in different people — sometimes rods first, sometimes cones first — is not fully understood. Because ARL6 is a rare cause of Bardet-Biedl syndrome, much of the human evidence comes from small case series and single cases, which limits how precisely the natural course can be described. How the different systemic features balance out for any one person, and how quickly they progress, remains difficult to predict.

As of this review, no therapy targeting the ARL6 gene itself has been approved. Most research to date has focused on understanding the biology in cells and animals and on describing the range of human features, rather than on gene-specific treatment. A drug called setmelanotide has been studied for the obesity and excessive hunger that can occur in Bardet-Biedl syndrome, but this addresses weight rather than the retinal disease and is not specific to the ARL6 gene. Researchers have noted that most people with this syndrome already have advanced retinal disease by early adulthood, which they describe as a narrow window for any future rescue treatment.

• An eye-specific version of the protein needed for vision

  Laboratory and animal research

  What was found:

  Removing BBS3L impaired vision and disrupted normal retinal structure, while the shorter form did not rescue these eye problems.

  Why it matters:

  It shows the gene has a specialized role in the retina, helping explain why vision is affected in this syndrome.

  Limitation: Findings come from fish and mice, not people, and do not by themselves describe a treatment.

• Discovery of ARL6 as the cause of Bardet-Biedl syndrome type 3

  Human genetic study (gene discovery)

  What was found:

  They found disease-causing changes in ARL6 in four unrelated families, identifying it as the BBS3 gene and the first small GTP-binding protein of its kind tied to human disease.

  Why it matters:

  This established ARL6 as a genuine cause of the syndrome and pointed to faulty cilia transport as the underlying problem.

  Limitation: It involved a small number of families and focused on identifying the gene rather than describing long-term outcomes.

• Retinal features in a Saudi Bardet-Biedl cohort

  Observational human cohort

  What was found:

  Most had advanced retinal disease and were legally blind by early adulthood, with cone-rod dystrophy the most common pattern and undetectable electroretinograms in nearly all.

  Why it matters:

  It gives a real-world picture of how severe and early the retinal disease can be and notes a narrow window for future rescue therapies.

  Limitation: A minority of families carried ARL6 changes, and the study did not find a clear link between specific variants and outcomes.

• A founder ARL6 variant on La Réunion Island

  Human genetic and population study

  What was found:

  A single shared ARL6/BBS3 variant, traced to a common ancestor about eight generations back, explained many local cases.

  Why it matters:

  It illustrates how the frequency of ARL6 disease depends heavily on ancestry and how this knowledge can guide local testing and counseling.

  Limitation: The findings apply to one specific island population and do not generalize to others.

• An unusual rod-sparing retinal pattern

  Single case report

  What was found:

  The picture matched a cone or cone-rod dystrophy, the first reported rod-sparing electroretinogram in a Bardet-Biedl patient with ARL6 changes.

  Why it matters:

  It adds to the known range of retinal presentations and shows that the eye pattern is not always the same.

  Limitation: A single patient cannot establish how common this pattern is.

Because ARL6 is linked to a syndrome rather than an eye-only condition, families may want to be aware that kidney problems, obesity, extra fingers or toes, and learning differences can be part of the picture and may benefit from monitoring. Onset often appears in childhood, so coordination between an eye doctor, a pediatrician, and a geneticist can be helpful for early planning. Because the condition is inherited in an autosomal recessive (definition: An inheritance pattern where a person needs an altered copy of a gene from both parents to be affected. Parents with only one copy are usually unaffected carriers.) pattern, siblings and other relatives may wish to discuss genetic counseling.

• Does my ARL6 genetic result explain a diagnosis of Bardet-Biedl syndrome, and which body systems should be checked?
• Which retinal tests would help track how my vision is changing over time?
• Given my particular ARL6 variants, what is known — and not known — about what to expect?
• Should I be monitored for kidney, weight, or other systemic features linked to this syndrome?
• Would genetic counseling be useful for my family and relatives?
• Are there registries or studies for Bardet-Biedl syndrome that I could learn more about?

Because ARL6 changes can point to a syndrome that involves more than the eyes, it is often helpful to confirm the genetic result and review whether kidney, weight, and developmental features should be monitored. In one reported case, a child originally thought to have an isolated retinal condition was later diagnosed with Bardet-Biedl syndrome after genetic testing, which underscores the value of a full evaluation. A retinal specialist and a genetic counselor can explain what a specific ARL6 result means and coordinate any additional specialist care. RP Hope's genetic testing resource explains what testing involves and what to ask.