A new study published in the Journal of Clinical Investigationbrings researchers one step closer to answering the question: Why do children with mutations in the same gene often experience very different symptoms?
A University of Calgary research team worked with clinicians and scientists across the globe to discover that mutations in CELF2, a gene linked to a rare group of neurodevelopmental disorders, are not all the same. Instead, different types of mutations affect the protein in different ways, helping explain why some patients develop seizures while others do not.
The team included Dr. Guang Yang, PhD;Dr. Micheil Innes, MD; PhD candidate Michelle Hua, BSc’21; and Isabel Clark, MSc’24
Since the team’s first CELF2 discovery five years ago, there have been only 30 patients with neurodevelopmental disorders linked to the CELF2 gene known globally. However, there are likely more undiagnosed cases. The study findings could help medical professionals provide an accurate diagnosis for those living with these rare conditions, which is a critical first step to guide personalized, effective treatments
Five years ago, your team first linked the CELF2 gene to neurodevelopmental disorders. What question were you trying to answer with this study?
University of Calgary
Dr. Guang Yang: When we first identified CELF2 as a disease gene, we knew it was associated with developmental disorders, but we didn’t know exactly how it was causing disease or why patients could look so different clinically
With many rare diseases, families see symptoms like developmental delays, speech impairments or seizures, but they don’t know what’s actually causing them. That makes diagnosis difficult and makes it even harder to think about treatment
Our goal with this study was to understand the biological cause of those symptoms. If we understand what’s happening inside the cell, we can start thinking about how to diagnose patients more accurately
For someone who’s never heard of CELF2, what does it actually do?
Yang: CELF2 is what’s known as an RNA-binding protein. You can think of it as a coordinator or gatekeeper inside the cell
Genes contain instructions for making proteins, but those instructions have to be carefully regulated. CELF2 helps control how those genetic instructions are processed and ultimately influences which proteins are made and when. Without that co-ordination, brain cells can’t function normally
Your paper describes CELF2 as “shuttling” between different parts of the cell. What does that mean?
Yang: Think of it as your workday at the office and being at home at the end of the day. At work you have one set of responsibilities and being at home you have another. Healthy living depends on being able to move between both places
CELF2 works the same way. It normally moves back and forth between the nucleus, the inner compartment of the cell, and the cytoplasm, the outer compartment. It performs different jobs in each location
If you stayed at work all the time, no one would be home to take care of your family. If you never left home, your work wouldn’t get done. CELF2 needs that same balance inside the cell
Michelle Hua
Courtesy Michelle Hua
Michelle Hua: CELF2 normally moves between the nucleus, which contains the cell’s genetic material, and the surrounding part of the cell called the cytoplasm. It has different roles depending on where it is located. Some disease-causing mutations prevent CELF2 from moving properly and cause it to remain in the cytoplasm. In neurons grown from patient cells, this was linked to unusually high levels of activity. This type of overactivity may help explain why some patients experience seizures
One of the biggest findings is that not all CELF2 mutations behave the same way. Why is that so important?
Yang: When we started the project to study CELF2 mutations, we thought they all lead to one disease condition. What we’ve discovered now suggests that there are actually at least two subgroups
That matters because accurate diagnosis is the foundation of treatment. If different mutations cause disease through different mechanisms, they may require different therapeutic approaches. For rare diseases especially, that’s incredibly important
Dr. Micheil Innes: This study confirms that knowing which gene is impacted is not enough information for rare disease patients and their families anymore. More precision is required; knowledge on the type of variant guides prognosis and treatment
Micheil Innes
Courtesy Micheil Innes
Your study also identified a drug pathway that reversed abnormal neuronal activity in patient-derived cells. How significant is that finding?
Hua: It’s an exciting finding because it gives us a possible direction for future treatments
We identified a signalling pathway that hadn’t previously been linked to these localization changes. When we targeted that pathway in patient-derived neurons, we were able to reverse the abnormal neuronal hyperactivity that we associate with seizures. This is an important step toward future therapies, but there is still much work to do before these discoveries can be translated into patient care
Families living with rare diseases often spend years searching for answers. How could these findings help them?
Innes: There are over 7,000 rare genetic diseases known. Patients and families undergo what we recognize now as a long diagnostic odyssey where first a rare genetic condition needs to be suspected then further referral and genetic testing. Once the rare variants are identified, we need to be sure that what we are seeing on the genetic testing fits with the patient’s symptoms, so this study goes a long way to clarifying what to expect with CELF2
This research involved collaborators around the world. Why was international collaboration so important?
Innes: Over the last 10 years, we’ve realized the importance of global matchmaking to connect clinicians, researchers and patients working on rare diseases. Since our first CELF2 discovery five years ago, there are still less than 30 known patients worldwide. We’re sure there are many more who can’t access the testing, or their doctors aren’t sure about the relevance of the variants found. We couldn’t have made these discoveries without our international connections
Isabel Clark
Courtesy Isabel Clark
Looking ahead, what excites you most about this research?
Hua: I think this opens the door to much more research into rare neurodevelopmental disorders and potentially other diseases involving RNA-binding proteins. Most importantly, it moves us one step closer to finding therapies for these patients
Isabel Clark: Patients with these ultra-rare conditions are finally being recognized. Many now have a diagnosis and a community they can connect with
Yang: As a basic scientist, it’s exciting to discover a new biological mechanism. But what’s even more rewarding is knowing that those discoveries may eventually help patients and families
Innes: Our initial observations in 2021 began with a single patient referred to the Alberta Children’s Hospital. To be able to provide precise diagnoses and prognoses, and soon we hope therapies to patients worldwide is an inspiring reminder that research is care.
This study fills an important knowledge gap, but it’s also just the beginning
Unlocking the Power of mRNA for Rare NDDs project is funded by the One Child Every Child Strategic Catalyst Grants and theAzrieli FoundationScience Grant. Led by UCalgary, theOne Child Every Childresearch initiative works to dramatically improve the lives of children, their families and maternal health across Canada. The initiative is funded by the Canada First Research Excellence Fund, with support from the Alberta Children’s Hospital Foundation and the Azrieli Foundation
Guang Yang is an associate professor with the departments of Medical Genetics and Biochemistry & Molecular Biology at theCumming School of Medicine(CSM) and holds a Tier II Canada Research Chair in Gene Regulation in Brain Development. He is a member of theAlberta Children’s Hospital Research Institute(ACHRI),Hotchkiss Brain Institute(HBI) andOwerko Centre for Neurodevelopment and Child Mental Healthat the CSM.
Micheil Innes is a professor in the departments of Medical Genetics and Pediatrics at the CSM. He is also a member of the ACHRI and HBI
Michelle Hua is a PhD candidate in the Biochemistry and Molecular Biology program at the CSM, under the supervision of Guang Yang.
Isabel Clark is a research co-ordinator with the department of Medical Genetics and ACHRI
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