Is 22q13 deletion syndrome a mitochondrial disorder?

David enjoying a walk in the park

Originally posted 19 September 2016
Updated 10 April 2024

Science is really interesting if you don’t let the details overwhelm you. Scientists master huge piles of details, but they always step back to see the big picture. They are truly fascinated with science. That fascination motivates their quest.  In this blog I will point out some really interesting facts so  you can share that fascination.

This blog is about organelles of the cell called mitochondria. If you look at cell with a high power microscope you will see something that appears to be another tiny organism living inside the cell.

Interesting fact #1: Mitochondria may have originally been single cell organisms that invaded larger cells.  Now, mitochondria are simply part of our cells.

Interesting fact #2: Mitochondria are the battery chargers of the cell. They turn sugars and oxygen into ATP.  ATP molecules are the rechargeable batteries used by the cell for nearly everything – from muscle contraction to digestion, growth and thinking.  Imagine what might happen if all your battery chargers were on the fritz. That would be a cell phone (mitochondrial) disorder with dramatic consequences.

Interesting fact #3: A paper published in January of this year shows that most people with 22q13 deletion syndrome have mitochondrial dysfunction (http://www.ncbi.nlm.nih.gov/pubmed/26822410).  Mitochondrial dysfunction affects more kids than any other problems except for intellectual and physical disabilities.

Interesting fact #4: Mitochondria are unique organelles because they operate using two separate sets of genes. One set of genes is on the regular (nuclear) DNA. The other genes are actually inside the mitochondria. These genes, mitochondrial and nuclear, operate together.

Interesting fact #5: mitochondrial genes come only from the mother, whereas nuclear DNA is an even mix of both parents. The term “mitochondrial gene” is confusing. Sometimes it means a gene from the mitochondrial DNA. Other times it means a nuclear gene that is needed to help the mitochondria work properly. In 22q13 deletion syndrome, a group of genes on chromosome 22 (nuclear DNA) are lost. Many of these genes are important to normal mitochondrial function. These are the mitochondrial genes I will discuss now.

The following genes impact mitochondria. I have written on several of these genes previously. This list includes the minimum size of a terminal deletion that would damage or delete the gene. The list is borrowed from my earlier blog (How do I know which genes are missing?).

Mitochondria related gene	Deletion size (Kbase)
CHKB	235.47
CPT1B	240.05
TYMP	288.47
SCO2	292.86
SELO	600.85
GRAMD4	4,180.53
TRMU	4,484.77
ATXN10	4,973.16
KIAA0930	5,577.70
SAMM50	6,821.94
TSPO	7,655.23
MCAT	7,675.07
BIK	7,688.76
ATP5L2	8,177.87
NDUFA6	8,727.69
SMDT1	8,735.12
ACO2	9,289.48

This list has 17 genes. About half the children with terminal deletions are missing 5.3 Mb (megabase) or more (see Understanding deletion size). That means half or more of our children are missing at least 8 mitochondrial genes. Have you met a child with a really large deletion? They generally have multiple major health issues. It is not clear which mitochondrial genes contribute the most to their problems, but even children with smaller deletions are outside the normal range of mitochondrial enzyme functioning.

Some of these genes likely have little or no impact. I have written about ATXN10 (Gene deletion versus mutation: sometimes missing a gene is better.). Some people inherit a mutated copy of ATXN10 that has an extra sequence.  It is an unused sequence that gets stripped off when the protein is produced.  The protein is normal. However, the excess stuff that gets stripped off interferes with another enzyme in the body. The interference ends up poisoning the mitochondria and killing the cells (http://www.ncbi.nlm.nih.gov/pubmed/20548952). Fortunately, this is not a gene we need to worry about.  Our children are missing ATXN10.  They don’t have the mutated gene seen in certain families. Likewise, based on what is know about the BIK gene, it is also unlikely to contribute to our children’s mitochondrial problems.

So, which mitochondrial genes are causing so many problems? One gene is specific for muscle function (e.g., CPT1B). We should not be surprised if that mitochondrial gene contributes to hypotonia (see 22q13 Deletion Syndrome: hypotonia). However, most mitochondrial genes are essential for normal function in every part of the body.

The degree of damage mitochondrial genes can cause can be seen with SCO2. Loss or damage to both copies is often fatal early in life (http://omim.org/entry/604377?search=sco2&highlight=sco2).  Perhaps more importantly, loss of just one copy of that same gene reduces essential enzyme activity and leads to behavioral defects in mice  (http://www.ncbi.nlm.nih.gov/pubmed/22900024). Thus, SCO2 could be a major contributor brain dysfunction in many children.

We know that more than half of our kids are outside the normal range of mitochondrial function. Many scientist believe that mitochondrial genes contribute to neurodevelopmental disorders (http://www.ncbi.nlm.nih.gov/pubmed/26442764), and that those disorders (e.g., 22q13 deletion syndrome) are associated with mitochondrial dysfunction (for example, http://www.ncbi.nlm.nih.gov/pubmed/26439018).  What is needed now is a more complete study that includes all of our children. How? When the scientific paper came out in January 2016 describing mitochondrial dysfunction in our children, I was certain the researchers would be invited to the 2016 conference. The head of that study was eager to come, present his results and gather more cheek swabs. That did not happen.

More recent studies have begun to highlight the relationship among mitochondria, inflammation, and PMS. These studies have led to an updated list of important genes of 22q13 (see this blog post).

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Some previous blogs

Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?
Mouse models
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Understanding deletion size
22q13 deletion syndrome – an introduction