Research Explained
Category: Research Explained
The CSNK2A1 Foundation explores the implications of Okur-Chung neurodevelopmental syndrome (OCNDS) on phenotype and genotype expansion. Learn about a novel frameshift variant discovered in a Chinese family and its potential impact on the clinical presentation of OCNDS.
Authors: Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey Publication Date: December 14, 2023 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Research Simplified Summary: The authors sequenced the DNA of individuals who had a rare disorder called Pituitary stalk interruption syndrome (PSIS), a condition that affects the pituitary gland, a crucial organ in the brain that regulates various hormones. They wanted to learn more about the potential genetic causes of PSIS. In individuals with PSIS, the pituitary stalk, a structure connecting the brain to the pituitary gland, is abnormally formed or absent. This disruption leads to hormonal deficiencies, including growth hormone (GH) deficiency, impacting growth, reproduction, and other bodily functions. Diagnosis often involves imaging studies, and management typically requires lifelong hormone replacement therapy to address the hormonal imbalances caused by the syndrome. The results of sequencing identified a single patient with Okur-Chung Neurodevelopmental Syndrome (OCNDS), harboring the most common CSNK2A1 missense variant, K198R. The child had the typical clinical phenotype of OCNDS including hypotonia, autism, and delay in the ability to walk. Major conclusions from this publication include the suggestion that obtaining a genetic diagnosis in cases of isolated PSIS will remain challenging and that PSIS is a disorder that should be considered when analyzing the full phenotypic spectrum of OCNDs in future studies.
Authors: Neil R. Ming, Deanna Noble, Steven Chussid, Alban Ziegler, Wendy K. Chung Publication Date: July 4, 2023 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Research Simplified Summary: This study surveyed a wide variety of patients with neurodevelopmental disorders through an online questionnaire through Simons Searchlight, a natural history study supported by the Simons Foundation. The study records data from medical records and captures caregiver responses about patients with neurodevelopmental disorders, including OCNDS. Oral health is an important area of study, as many individuals with neurodevelopmental disorders have poor oral hygiene and broader dental abnormalities. 620 caregiver responses to the survey were recorded across 39 genetic neurodevelopmental disorders, with most surveys completed on behalf of children. 145 siblings of these patients without neurodevelopmental disorders served as a group to compare any findings against. Overall, the patients with neurodevelopmental disorders were found to display increased drooling, difficulty receiving dental care, late arrival of baby teeth, and abnormal growth of both baby and permanent teeth. Among the 39 genetic disorders tested, only patients in four groups, including OCNDS, were found to be more likely to have any specific dental issues when compared to the sibling control group. Of note, OCNDS was found to be associated with an increase in anomalies found in baby teeth, including long incisors, cracked teeth, missing enamel, small teeth, and fused teeth. Importantly, this is the first time that OCNDS has been associated with abnormal tooth development, indicating a potentially unmet need for improved dental care and surveillance in OCNDS patients.
Authors : Newell Belnap, Aiai Price-Smith, Keri Ramsey, Kamawela Leka, Anna Abraham, Emma Lieberman, Katie Hassett, Sai Potu, Natasha Rudy, Kirstin Smith, Fady M. Mikhail, Kirstin G. Monaghan, Andrea Hendershot, Jeroen Mourmans, Maria Descartes, Matthew J. Huentelman, Jennifer Sills, Sampath Rangasamy, Vinodh Narayanan Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Research Simplified Summary: In this study, researchers profiled and compared OCNDS symptoms present within and across three families. This report is the first study of families with OCNDS inherited by children from their parents, instead of the more common inheritance pattern where the OCNDS genetic variant is new and only is present in the child. This report also confirms that both men and women with OCNDS are fertile. When comparing each of these families, there was a striking difference in the symptoms experienced by each parent and child, even though the OCNDS genetic variant is the same. For example, two half-sisters (individuals that share only one parent) in a family with OCNDS experienced vastly different effects with one displaying behavioral issues, musculoskeletal problems, growth irregularities, and difficulty feeding among other symptoms that were present but much less severe in their half-sister. When comparing across families, symptoms were even more divergent, despite two families having the same disease-causing DNA variant. Although both families displayed the p.Lys198Arg (K198R) variant in the CSNK2A1 gene, the most common disease-causing variant found in OCNDS patients, one of the families had multiple cases of generalized muscle weakness (hypotonia), while the other instead experienced behavioral issues. Together, this report shows that OCNDS symptoms vary greatly even within individuals with the same genetic changes causing OCNDS. These symptoms also varied within families, indicating that it is unlikely that researchers will be able to correlate specific OCNDS-causing DNA variants with specific symptoms. More generally, these findings indicate that there may be many people with undiagnosed OCNDS throughout the world due to the varying severity of symptoms and therefore varying diagnosis/treatment needs. Learn More
Authors : Mohamed Wafik, Heidi Kuoppamaa, Priyal Hirani, John Hignett, Suzanne Lillis, Karine Lascelles, Shweta Sardesai, Kumudini Gomez, Muriel Holder-Espinasse Research Explained By: Gabrielle Rushing, PhD Research Simplified Summary: This study was a short case report explaining the discovery of two new DNA variants in the CSNK2A1 gene that are causative for Okur-Chung Neurodevelopmental Syndrome (OCNDS). The individuals who had these new DNA changes showed milder symptoms compared to what was known before. One patient had seizures but didn't experience any delays in their development. The other patient had some differences in their physical features like a smaller head and low-set ears. They also had mild delays in their development, but they were doing well in regular education programs and didn't have seizures. This report shows that OCNDS can vary in the symptoms people experience and how severe those symptoms are. It also emphasizes the importance of finding new patients and involving affected individuals in research. This will help us understand the range of symptoms better and make connections between the DNA changes and the type of symptoms that appear. By improving our understanding of how these DNA changes affect the symptoms, we can develop better strategies for treatment in the future. Learn More
Authors : Demetra Ballardin, Jose M. Cruz-Gamero, Thierry Bienvenu and Heike Rebholz Publication Review Explained By : Demetra Ballardin, Barbara Lecis Cocco, Jose Cruz-Gamero and Heike Rebholz Publication Review Explained Summary : OCNDS and POBINDS are two neurodevelopmental disorders that are caused by alterations in two genes that encode the blueprint of two different components of a protein called CK2. CK2 consists of two parts, a regulatory subunit that is termed CK2beta and the catalytic one that performs a biochemical reaction in our bodies, termed CK2alpha. OCNDS is caused by an alteration in the gene for CK2alpha, and POBINDS by alterations in the gene CK2beta. The two conditions are similar in many aspects, but also have differences, and in the literature thus far were never directly compared. With our review, we wanted to bring together patients’ data from both disorders in order to compare their symptoms and, via a literature survey, try to reason how known cellular function of CK2 could explain common and specific symptoms of both syndromes. It is not surprising that we observed that OCNDS and POBINDS patients share many symptoms, including growth deficits, neurological and behavioral problems. However, the syndromes also present important differences: OCNDS patients achieve their developmental milestones (onset of speech and walking) much later and have a higher prevalence of intellectual disabilities and stereotyped movements than POBINDS patients. However, POBINDS patients suffer more often from epilepsy, and this includes a high prevalence of generalized tonic clonic seizures that are often difficult to manage pharmacologically. OCNDS patients do not suffer from generalized tonic clonic seizures, but other, milder forms of seizures. Moreover, OCNDS patients present sleep disturbances and gastrointestinal issues that were not reported by POBINDS patients. We also tried to link certain symptoms such the loss of muscle tone and behavioral symptoms to known roles that CK2 plays in our brain, highlighting interesting processes that will be further studied to better understand OCNDS and POBINDS, and that could be the focus of therapeutic approaches. Studies using patients’ cells, mouse models and other models systems of the conditions will help to understand, on a molecular level, the similarities and the important differences between OCNDS and POBINDS.
Link to Paper: https://doi.org/10.3389/fmolb.2022.831693 Authors: Werner C, Gast A, Lindenblatt D, Nickelsen A, Niefind K, Jose J, and Hochscherf J Research Explained By : Dr. Jennifer Hochscherf Research Explained Summary : Patients with OCNDS have a change or mutation in the gene that contains the blueprint for the protein “protein kinase CK2alpha”. There are always two copies of this gene in the cell and the mutation only occurs in one of them. The blueprint determines the sequence in which different building blocks, so-called amino acids, are linked together in a long chain. However, this long chain should not be thought of as a straight thread, but rather it takes on a spatial three-dimensional structure that is determined by the sequence of the building blocks. This three-dimensional structure is crucial for the function of proteins. The protein CK2alpha is an enzyme, a protein kinase to be more specific. Enzymes are tools of the cell to assist and catalyze chemical reactions. The CK2alpha reaction is the chemical modification of a second protein (the so-called “substrate protein”) by attachment of a phosphate group. This “phosphorylation” event is a metabolic signal with several possible consequences for the substrate protein: for example, it can be switched on or off, it can be marked for degradation or for transport to a specific location within the cell. In summary: correct and carefully out-balanced cellular phosphorylation reactions by CK2alpha and other protein kinases are crucial events to keep cells healthy and beneficial for the whole organism. CK2alpha can phosphorylate different substrate proteins, and it recognizes them by a specific amino acid sequence on their surface. It is most important that this recognition works well and that the substrate proteins of CK2alpha are not mixed up with those of other protein kinases. To assist this job, CK2alpha has a binding partner called CK2beta. Together, they form a stable complex, the so-called CK2 holoenzyme, which in total consists of two CK2alpha and two CK2beta proteins and which is the predominant form in the cell. In our research, funded by the CSNK2A1 foundation, we aimed to elucidate the consequences of the most common mutation reported for OCNDS patients, which leads to the exchange of the amino acid lysine at position 198 to arginine in CK2alpha (CK2α Lys198Arg ). We therefore examined several aspects of the CK2α Lys198Arg variant, such as the subunit interaction, stability, three-dimensional structure and activity and compared them with the non-mutated form, the “wild type”. We found that the mutation does not affect the interaction with CK2beta, and that the thermal stability of the protein is even slightly increased. We applied a technique called X-ray crystallography that enables to determine and visualize the three-dimensional structure of a protein with near to atomic resolution to investigate the molecular details of the CK2α Lys198Arg structure. The mutated position 198 is located in the substrate recognition site of CK2alpha that exposes a positively charged surface area and preferentially binds negatively charged residues of its substrate proteins. In a CK2alpha X-ray structure solved in the absence of a substrate protein, the positively charged region is often occupied by two negatively charged sulfate ions. These sulfate ions thus mark the binding sites for negatively charged amino acid building blocks in the substrate protein that belong to the sequence recognized by CK2alpha. The most striking feature of the CK2α Lys198Arg structure is that the position of one of the characteristic sulfate ions is shifted compared to the wild-type. Although this shift of the anion binding site seems subtle at first sight, this structural finding supports the conclusion drawn by Caefer et al. (2022) that the CK2alpha mutant Lys198Arg does not primarily lead to a loss of function, but to a change in substrate specificity. To detect possible selectivity changes due to the Lys198Arg mutation, comprehensive enzymatic activity assays have been performed in Prof. Joachim Jose’s research group at the University of Münster, Germany. The outcome of these assays support the conclusion by Caefer et al. (2022) that the substrate spectra of CK2α Lys198Arg and wild-type CK2alpha differ from each other, meaning that CK2α Lys198Arg has some substrate proteins not phosphorylated by wild-type CK2alpha and vice versa. In particular proteins of the nervous system might be differentially phosphorylated by the variant CK2α Lys198Arg and the wild-type form. Understanding the molecular basis of OCDNS is important to identify the direction in which research should continue and ultimately to develop strategies for the development of therapies. Link to: Caefer et al. (2022) The Okur-Chung Neurodevelopmental Syndrome Mutation CK2K198R Leads to a Rewiring of Kinase Specificity. Frontiers in Molecular Biosciences. https://doi.org/10.3389/fmolb.2022.850661 If you have any further questions, please contact Jennifer Sills at jennifer@csnk2a1foundation.org Jennifer Hochscherf I received my PhD in biochemistry from the University of Cologne in 2009 on the molecular interactions of CK2 and subsequently joined the laboratory of Prof. David Litchfield at the University of Western Ontario in London, Canada as a postdoctoral fellow. I then returned to Cologne to the laboratory of Prof. Karsten Niefind as a postdoc, with interruptions as an experienced researcher at the company Kinase Detect in Odense, Denmark and as a lecturer at the University of Cologne. Since my PhD thesis, my research is focused on the protein kinase CK2. Currently, my focus is on the characterization of CK2alpha and CK2beta variants associated with the neurodevelopmental disorders OCNDS and POBINDS. I am particularly interested in the 3D structures of proteins and the biophysical characterization of protein-protein interactions as well as the interaction of proteins with small molecules.
Link to Paper : A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability | PNAS Authors : Abdelhalim Loukil, Chloe Barrington, and Sarah C. Goetz Research Explained By : Sarah C. Goetz. PhD, Abdelhalim Loukil. PhD Research Explained Summary : Primary cilia are tiny projections present the surface of our cells that act like an antenna: They help cells receive signals from their surroundings and respond by activating certain cellular programs. These programs are important to control the development of embryos and the functioning of tissues in the human body. Because of this, genetic changes that cause defects in the structure of cilia lead to many different human genetic disorders. The cilium assembles from an organelle called the centrosome, which forms the base of the cilium. Surprisingly, we found that CSNK2A1 is enriched at the base of the cilium, implicating it in the regulation or functioning of cilia. We found that the deletion of the Csnk2a1 gene from cells causes structural defects in the cilia: they become abnormally long and break more easily at the tip, which makes them less stable. Altogether, we found that CSNK2A1 is critical to maintaining normal movement of cellular materials inside the cilium, and for preserving the stable structure of cilia. We also tested whether the changes to CSNK2A1 that are linked with Okur-Chung neurodevelopmental disorder (OCNDS) might affect cilia. When we introduced known CSNK2A1 mutations into cells, this led to abnormal cilia shape, suggesting the OCNDS changes might interfere with the functioning of cilia. These findings highlight a potential linkage between CSNK2A1 function in regulating cilia and OCNDS. Our ongoing work will further describe this link and uncover its molecular basis. If you have any further questions, please contact Jennifer Sills at jennifer@csnk2a1foundation.org
Link to Paper : https://rdcu.be/cjYNS Authors : Dominguez I, Cruz-Gamero JM, Corasolla V, Dacher N, Rangasamy S, Urbani A, Narayanan V, and Rebholz H Research Explained By : Dr. Heike Rebholz Research Explained Summary : All patients diagnosed with OCNDS share one thing in common: they have one change in the gene that encodes for a protein called CK2. There are two genes that encode the genetic blueprint for CK2 in every cell, and in OCNDS one of them has such a change, also called mutation. We know that approximately 30 patients are reported in scientific journals, but that there are many more patients all over the world. Thus far, 16 different genetic changes, all in the same gene, have been described in the literature. However, to date, nobody knew how this change actually affected CK2 itself, how and if it altered its ability to perform its function in every cell of our body. We wanted to answer this question and, to achieve this, produced the unmutated and 16 different “mutated genes” which we then expressed in bacteria and also in cultured mammalian cells. We found a reduction of activity for all of the 16 CK2 mutations. CK2 is a kinase, that is a protein whose job is to alter other proteins in the cell by adding a phosphate group to them. Thus, our findings indicate that, in OCNDS, the mutation renders CK2 less able to perform such phosphorylation events. It is encouraging, however, that this loss of activity does not have a large overall impact on the general health of cells used in our studies and that important proteins that are known to be modified by CK2 are not necessarily affected. What that means is that at least in some cases, the remaining healthy and “unmutated” version of CK2 can compensate for the one, “mutated” copy of CK2. We further found that very few of the mutations also lead to changes in the localization of CK in the cells. While our findings are very basic and not directly applicable to the clinic, the question of CK2 activity had to first be addressed and will allow for further studies. The search now focuses on identifying the actual proteins that are affected by the mutation and are responsible for the disease-characteristic symptoms. This will bring us a big step closer to better understanding what happens in the condition and ultimately will identify proteins, which can be therapeutically targeted and lead to new treatments. If you have any further questions, please contact Jennifer Sills at jennifer@csnk2a1foundation.org
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By Penelope Gatlin October 2023 When our son was born in 2012, he was hypotonic, severely jaundiced, had feeding difficulties and features such as epicanthic folds and small low set ears. We were told immediately that doctors had suspicions of a genetic syndrome. At that time, genetic testing was limited and once abnormal karyotype, Trisomy 21, and Fragile X were ruled out, we left the hospital with an 8 day old and no diagnosis. While no testing was available at that time to identify the ultra-rare syndrome my child had, because it wouldn’t even be identified until 4 years later, I can only imagine the difference it would have made to our journey to have such an answer sooner. Instead, we were unprepared and actually unaware that just because a diagnosis hadn’t been made then that it didn’t mean there wasn’t in fact a rare disease present. Instead, we dealt with issues as they came and worried and wondered what would be next. From feeding issues and reflux and constipation, to low muscle tone and delayed walking, to speech delay, social and emotional delays, toileting delays, diagnoses of developmental delay, anxiety, situational mutism, sensory processing disorder, and autism, until finally genetic testing that revealed the diagnosis that we’d waited 7 years to find out. While receiving a diagnosis can seem scary, not having an answer but knowing there must be one is even more so. In 2019, the day I clicked onto the portal to see the test results, the largest word on the page was POSITIVE. My heart stopped for a second. For the first time, I read the words “Okur-Chung Neurodevelopmental Disorder.” A roller coaster of emotions ensued, including sadness that we hadn’t known this from birth because it would have made us as parents more prepared, and given us more understanding about what might arise next. Relief that we had an answer, grateful that this syndrome had been identified and that he was among one of the first hundred diagnosed with it in the world, and glad we had the privilege to have access to the testing. Excitement that we can participate in future research. Fright that there’s so much we don’t know about OCNDS, and happiness that there is something that we do. A feeling that we are no longer shooting in the dark and have a small but supportive community to rely on and learn from. I am hopeful that one day, all newborns with features like my child will be tested at birth, so parents can have access to the answers, support, and interventions and therapies that can best help their child as soon as possible.
For 16 years, my child displayed numerous symptoms that left us searching for answers, but a genetic diagnosis remained elusive. I considered having my child evaluated for autism to shed light on their situation. However, when I reached out to teachers, doctors, and therapists, I received frustrating responses: “Your child is too friendly to be autistic.” This statement made me doubt the possibility of autism because my child was sociable. “Your child can transition from one activity to another – they are not autistic.” Hearing this, I questioned whether my child’s ability to shift activities invalidated the need for an autism evaluation. “Your child can look me in the eye and answer questions – they are not autistic.” Observations like this made me second-guess the idea of autism, even though my child faced various challenges. “Getting a diagnosis that does not apply to your child would be a big waste of money.” Despite my persistent concerns, this cautionary advice about the evaluation costs left me hesitant. We finally pursued an evaluation when my son turned 20, and it confirmed that he is indeed on the autism spectrum (severe side). Looking back, I regret not taking this step sooner. I should have pursued the autism diagnosis before we received the genetic diagnosis. There are several benefits we could have gained as a family if we had pursued an early diagnosis: “Early Support Is Crucial:” I now realize that early intervention could profoundly impact my child’s development. We could have accessed the right services and therapies much earlier with a diagnosis. “Understanding My Child Better:” I struggled to comprehend my child’s behaviors and communication difficulties. An earlier diagnosis could have provided insights into their unique needs and thought processes. The education could also help me explain how to react to my child’s behavior to family members. “Tailored Guidance and Resources:” A diagnosis could have opened doors to specialized resources and guidance, enabling me to provide the best possible support for my child. “Connecting with Others:” Being part of the autism community might have connected us with other parents who understand our experiences. Sharing and learning from each other could have been invaluable. “Planning for the Future:” Knowing more about my child’s strengths and challenges could have helped me better plan their future, including education, career, and overall well-being. Depending on your location, many states offer funding and support if your child has an autism diagnosis. I wish I listened to my voice instead of being swayed by experts who didn’t fully understand my child’s situation. Ultimately, I know this decision is significant, requiring careful consideration by parents. Looking back, I wish I had trusted my instincts and sought an evaluation sooner to improve my child’s life.
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