PACS2 gene consists of around 100 thousand nucleotides.
PACS2 syndrome is caused by one of two point mutations: c.625G>A (p.Glu209Lys) or c.631G>A (p.Glu211Lys). It means: one of 100 thousand letters (nucleotides) was exchanged for the other. One small mistake leading to massive consequences.
What does it mean in practice? At position 625th or 631st of PACS2 gene, nucleotide called guanine (G) was changed for adenine (A). In this specific places, guanine was part of 3-letter-set “GAG” coding Glutamic acid (Glu). Exchange for adenine resulted in change of the code to “AAG” and this code leads to production of Lysine (Lys). Due to that, the structure of the protein is impaired.
Why this specific place is so important? We do not actually know. However there are some hypothesis based on what we know about wild (“healthy”) PACS2 gene.
PACS2 protein is called sorting protein. What means that it is like a gatekeeper between different cell departments, specifically mitochondria and endoplasmic reticulum, helping some other proteins to enter in and out between those departments. And especially the area where PACS2 syndrome-related mutation happens is somehow connected to this “transportation” function.
At the same time, while most of amino acids are neutral, glutamic acid has acidic nature (has positive charge) while lysine has alkaline nature (has negative charge). It is then not only small change of one amino acid to another, it is the change of electric charge in potentially critical place for connection with other proteins. In this set-up our “gatekeeper” is kind of drunk – may be more eager to hug and for a longer time with some people who should not enter or should enter faster. Or may completely overlook those who are necessary for mitochondria function. Etc. Those details we don’t know for sure, but definitely, it causes the problem in “relationship creation and maintenance”. Saying it more scientifically: “[the mutation] alters binding of PACS2 to one or more client proteins critical for neuron communication, neurogenesis, or cerebellar development”.[1]
PACS2 protein in general plays key role for functioning of Mitochondria-associated ER membrane (MAM). It is the structure critical for communication of those 2 departments. And calcium channel is key for this. There is strong hypothesis that PACS2 syndrome is caused (at least partly) by disturbance of calcium channel crosstalk and from there, it is a straight way to epilepsy [2] (however there are more hypothesis explaining epilepsy in PACS2 syndrome). [1]
PACS2 protein is expressed (needed the most for function) of brain (especially oligodendrocytes) and spinal cord cells. That explains why our children have hypotonia and changes in cerebellum, but also why they experience problems with learning – oligodendrocytes are critical for mylenation and myelination is simply “concreting” of what we learn. If the process of myelination is impaired, our children need thousands more repetitions to learn something.
There are still more questions than answers regarding the specific mechanism of action behind PACS2 syndrome, and that is what we, as the PACS2 Research Foundation, explore with our partners. The Nencki Institute of the Polish Academy of Sciences researches metabolic processes, delving into even more detail to determine whether lipid metabolism – crucial for brain development and myelination – is disrupted. They analyze calcium homeostasis with a focus on mitochondria, and examine the representation of other proteins, observing if they are present in mitochondria in either excessive or insufficient amounts. The teams engaged in Nencki Institute are specializing in lipid metabolism and mitochondria – one of them is called “Mito-lab”, and they really are mitochondria-freaks 😊 – the best address for mutation impairing mitochondria homeostasis.
Alicia Guemes-Gamboa from Northwestern University (Chicago), together with her team, is preparing to analyze the development of neuronal cells. She has already published two notable papers, providing insights into the homologous gene PACS1 and disease related to mutation in this gene. She knows where to look at first, as there are similarities between PACS2 syndrome and PACS1 syndrome (both involve point mutations in sensitive gene regions, are related to sorting proteins, and share similar patient phenotypes etc.[4]). Consequently, we maintain regular contact with the PACS1 Syndrome Research Foundation and have recently been invited to their scientific conference scheduled for May 2024. They initiated their work four years earlier, and we are hopeful that, thanks to their experience and robust research plan, we can accelerate our progress in finding answers for PACS2 syndrome.
What about other mutations of PACS2 gene?
There are a few children having deletion of PACS2 gene (including deletion of some additional genes), which leads to similar, however much more severe, symptoms as PACS2 syndrome. It is not sure how much of phenotype (visible symptoms) is impacted by missing PACS2 gene and how much by combination of it with other genes missing as well. Nevertheless, there are individuals reported who has “stop”-mutation in PACS2 gene, meaning, the PACS2 protein is not produced in full (but only this one), and they are relatively healthy.
There are also children with point mutations in PACS2 gene but in different area – all cases we know personally or are reported in global gene bases are people who reach independence in adult life. There is no intellectual disability observed or significant motor problems, however they may have some behavioral difficulties and epilepsy.
[1] Olson H. E., at all., A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis, https://www.cell.com/ajhg/fulltext/S0002-9297(18)30094-6
[2] Truong Thi My Nhung, at al., Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66, https://pubmed.ncbi.nlm.nih.gov/37523531/
[3] Human Atlas, RNA expression, https://www.proteinatlas.org/ENSG00000179364-PACS2/tissue#rna_expression
[4] Sakaguchi Y., at al., Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis, https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.62020
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