Is 22q13 deletion syndrome a ciliopathy ?

David 8 June 2015
David wearing his Roots, Rock, Reggae tee shirt.

What makes humans special?

There are different ways we, as humans, think of ourselves as special.  Of course, our children are special.  That goes without any further discussion.  But, as a species, special seems to come in a number of flavors.  Much of it centers around our flexible thinking and strategic planning. For example, one theory is that our brain allows us to plan and execute cooking.  Cooking provides concentrated nourishment essential for brain expansion (Warneken and Rosati, 2015). Of course, spoken language with complex syntax and hypothetical context is unique among humans. Other than being a funny-looking primate (upright walking and rather hairless), most of what makes us human is related to our brains: intellectual ability, sophisticated social interactions, symbols, language and future planning.

In the prior posting (“Understanding translocations in 22q13 deletion syndrome“) I explained how evolution opens new opportunities by duplicating a gene (creating paralogs).  One gene can remain in its original job and the other copy can mutate to find a new role. Once a gene has diverged into two genes, another wonderful door opens.  We have about 20,000 genes in our DNA, but we have about 800,000 ways to regulate when and where those 20,000 genes are used. So, not only is a paralog free to mutate, but where it is used and when it is used are now open to evolutionary pressures. In our example from last time, hypothetical gene L1 kept its original function while L2 took on a new role.

Even science makes mistakes

Not long ago, scientists comparing single-cell organisms with more recent animals noted that the whip-like tail (called flagella) used by bacteria, euglena and sperm to “swim”, did not exist on most cells of complex organisms, like mammals. There are a few places where we mammals use flagella. We use a version called microvilli to stir foods in the intestine.  Flagella are used by sperm.  Mostly, however, our bodies don’t use flagella. Yet, nearly every cell in our body has a tiny hair-like appendage structurally similar to flagella.  They are called cilia.  Scientists once decided that these were unimportant leftovers (fastigial organelles) from our swimming ancestors.  They were wrong.

Primary cilia in neurodevelopmental disorders Enza Maria Valente,Rasim O. Rosti,Elizabeth Gibbs& Joseph G. Gleeson Nature Reviews Neurology 10, 27–36 (2014)
Primary cilia in neurodevelopmental disorders
Enza Maria Valente, Rasim O. Rosti, Elizabeth Gibbs & Joseph G. Gleeson
Nature Reviews Neurology 10, 27–36 (2014)

Cilia are no laughing matter

Now that science is older and wiser we know that cilia are critically important organelles.  They are the nose of the cell, sniffing out molecules in the extracellular environment.  Most cilia it seems, have lost their hardware for swimming.  In doing so, they have gained the ability to provide specialize chemical interaction with other cells in the environment.  Free from their motile past, cilia have evolved into critical components of the body, including the rod and cone photoreceptors that give us the ability to see.  Cilia are very much like synapses (see drawing).  They have complex networks of proteins that create a special assembly for cell-to-cell communications.  Proteins are selectively transported to and from the membrane and the membrane has receptors like a synapse.  Also like synapses, mutations or deletions of genes that build or regulate cilia function can lead to partial or complete neuronal (i.e., brain) dysfunction (Metin and Pedraza, 2014; Valente et al., 2014).

Cilia are part of every neuron in the brain. They regulate where neurons go and which other neurons they contact during the dance of prenatal brain development.  They regulate brain growth, respond to inflammation and probably regulate many of the changes associated with puberty and aging.  Cilia are so important that there are now a series of syndromes recognized as ciliopathies: diseases/syndromes clearly caused by the deletion or mutation of a gene used within the cilia.  Is 22q13 deletion syndrome a ciliopathy?  There is reason to suspect so.

RABL2B somehow makes us human

There is a gene sitting on the very end of chromosome 22 that is deleted in every case of 22q13 deletion syndrome caused by a terminal deletion. Let me repeat that: every child with a terminal deletion is missing RABL2B.  Until recently, scientists had no idea the importance of this gene. RABL2A and RABL2B are paralogs of RABL2 found in nearly all mammals.  In rodents there is one role that has been studied: this gene is necessary to build working sperm tails (Lo et al., 2012). Male mice missing RABL2 do not seem to be very impaired, but they are sterile because of defective flagella.  Before the importance of cilia was fully understood, researchers studying 22q13 deletion syndrome assumed that RABL2B was not an important brain gene.  However, now we know two new things about RABL2B.  First, RABL2A and RABL2B can only be found together in primates, and only in primates with big frontal lobes: chimpanzees and humans (Wong, 1999).  Large frontal lobes might have been impossible without the duplication of RABL2 into the two paralogs RABL2A and RABL2B.  However, humans are much smarter (IQ equivalent) than chimpanzees.  And, only in humans, RABL2B is expressed at a disproportionately higher level in the brain than RABL2A (Kramer et al., 2010).  RABL2B is not a sperm motility gene (although it may contribute to sperm motility).  It is specialize for assembly of the cilia in the brain.  It is somehow important for what makes humans, human.

How does one study a gene so unique to humans?

Some genes are easy to study.  If my research was in molecular genetics, I would look for a large, popular gene that has a known function and can be knocked out in rodents.  Why bang my head against the wall working on a difficult gene?  RABL2B is difficult.  It does not exist in rodents.  It is small, so it is harder to pick up on gene microarrays/chips.  The RABL2A paralog is so similar to RABL2B that distinguishing between the two genes is difficult. RABL2B expression is a critical feature of brain function in humans, and expression regulation is more difficult to study than simply mutating a gene to see what happens. There are fewer tools for studying cilia than studying the nucleus or the synapse.  All-in-all, figuring out the exact role of RABL2B in the human brain will be inconvenient.  Molecular biologists steer away from unpopular genes that are difficult to study.  Unless we incentivize the study of RABL2B, we are unlikely to ever learn what damage its deletion does to our children.  Treatments and drugs aimed at other genes could end up being a waste of time if we are not prepared to understand and mitigate the impact of RABL2B.

A connection between RABL2B and IGF-1?

A very recent study of cilia (in fat cells) has demonstrated a link between IGF-1 receptors and cilia. As fat cells mature their cilia develop IGF-1 receptors, presumably to regulate fat cell growth (Dalbay et al., 2015).  It is not a stretch to expect that cilia in the brain have similar IGF-1 receptors. That means, giving IGF-1 to patients with 22q13 deletion syndrome may be ineffective if loss of RABL2B interferes with cilia formation and IGF-1 detection.

RABL2B and seizures

Cilia sample the extracellular environment (fluid space between neurons) and allow the neurons and other brain cells (e.g., astrocytes) the opportunity to respond to pathological conditions.  Seizures are an example of a pathological condition that impacts the extracellular environment:  seizures are associated with excess extracellular glutamate.  Extracellular glutamate can be damaging (Coulter and Eid, 2012).  From this perspective it is not surprising that ciliopathies are often associated with seizures (e.g., Oral-Facial-Digital Syndrome Type I).  About 30% of individuals with 22q13 deletion syndrome experience seizures.  Given the severity of seizures in some of our children, it seems likely that loss of RABL2B either precipitates seizure activity, or worsen seizures events by interfering with a cell’s response to extracellular chemical events. Many people with 22q13 deletion syndrome take seizure medications, which work for a while, then cease to provide benefit. Perhaps problems with cilia are responsible for making these medications lose effectiveness over time.

Why are there not clinical cases of RABL2B causing 22q13 deletion syndrome?

Thus far, there are no cases of 22q13 deletion syndrome where only RABL2B has been mutated or deleted.  (Although, every case of terminal deletion is missing RABL2B.)  One possible case of RABL2B deletion was reported, but further examination showed it was a more typical larger terminal deletion (see Patient 31 in Bonaglia et. al, 2011).  The problem in finding  a patient missing only RABL2B is two-fold.  First, most genetic tests cannot find a mutation or microdeletion in RABL2B.  The gene is small and most arrays/chips do not sample that gene sufficiently (if at all).  Exome sequencing can find a mutation or deletion, but geneticists have already convinced themselves that RABL2B is not an important gene.  Geneticists are likely to treat any mutation of RABL2B as irrelevant.  That is rather ironic, considering it would be relevant to the one-thousand patients with 22q13 deletion syndrome who are missing this gene.



Previous posts:
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction


6 thoughts on “Is 22q13 deletion syndrome a ciliopathy ?

  1. Regarding your statement: “Many people with 22q13 deletion syndrome take seizure medications, which work for a while, then cease to provide benefit.” Are you saying that anti-seizure medication eventually loses its effectiveness in every person with 22q13 deletion?


  2. I was reading this and when I got to the part regarding seizures it really struck a cord. I have had extremely bad grand mal seizures all my life and have been on one medication after another. I even had to go to the Mayo Clinic at one point when I was in my 20’s. Where they diagnosed me as having Beche’ts. The medications would work for a while and then the seizures would be back with a vengeance.


    • Behcet’s syndrome is an inflammatory disease that may be autoimmune. There may be an inflammatory component to seizures in 22q13 deletion syndrome, as well. In both cases, the best treatments are yet to come after understanding the genes and mechanisms that cause the inflammation.


  3. It was very informative to read about the cilia and RABL2B, in general, and especially in regard to our 22q13 Deletion children. Let’s hope some researchers with the needed expertise get invigorated by your post and begin the difficult work of better understanding RABL2B in humans. And a huge thank you for layman-tizing (a new word!) your posts so I can more readily understand the content.


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