Research Explained: Translating CSNK2A1/OCNDS Advances for Families

Learn about a novel CSNK2A1 frameshift variant linked to stillbirth. Join us in advancing research for Okur-Chung Neurodevelopmental Syndrome.

Learn about prenatal diagnosis of Okur-Chung Syndrome, ultrasound findings, & genetic implications. Join our mission for a cure.

This research explores clinical and genetic findings in 15 Turkish patients with Wiedemann-Steiner syndrome, identifying novel KMT2A variants and highlighting the importance of advanced testing for accurate diagnosis.

This research shows that core features of OCNDS remain consistent across genetic variants, while mutations in key protein loop regions are linked to a higher symptom burden and earlier diagnosis.

Study overview of 226 children with epilepsy showing how genetic causes shape ketogenic diet response, including a notable seizure-free CSNK2A1 case.

Explore a complex case of adrenal hypoplasia & OCNDS. Learn about diagnosis challenges & the need for thorough evaluations.

A rare case study explores dual diagnosis of Okur-Chung Neurodevelopmental Syndrome and Becker Muscular Dystrophy, highlighting the importance of comprehensive genetic testing when symptoms go beyond a single condition.

Explore a novel CSNK2A1 variant in a Turkish patient with Okur-Chung Syndrome. Join us in advancing research for effective treatments.

Learn about the link between microcephaly & CSNK2A1 gene variants in Okur-Chung Neurodevelopmental Syndrome. Support ongoing research efforts.

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 Link to Paper: https://onlinelibrary.wiley.com/doi/10.1111/cge.14408 Research Explained 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.

Authors: Mitsuko Nakashima, Jun Tohyama, Eiji Nakagawa, Yoshihiro Watanabe, Ch’ng Gaik Siew, Chieng Siik Kwong, Kaori Yamoto, Takuya Hiraide, Tokiko Fukuda, Tadashi Kaname, Kazuhiko Nakabayashi, Kenichiro Hata, Tsutomu Ogata, Hirotomo Saitsu, Naomichi Matsumoto. Publication Date: January 17, 2019 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/s10038-018-0559-z Research Explained Summary: This case report describes four patients with neurodevelopmental disorders, united by their recurrent seizures. Two of these patients were confirmed to have OCNDS, while the other two have Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS). These disorders are caused by mutations in the CSNK2A1 (OCNDS) and CSNK2B (POBINDS) genes, which encode the proteins CK2α and CK2β. Genes are the molecular blueprint for proteins, which perform functions required for life. These proteins bind to each other and create a larger complex of proteins known simply as CK2. CK2 is an enzyme, meaning that it facilitates chemical reactions in a cell, potentially affecting many other proteins – CK2α performs these chemical reactions, while CK2β helps regulate the function of CK2 overall. The authors describe these patients in depth and review previously published cases to draw conclusions about what unites and separates these two diseases. Here, we will focus on their description of the patients with OCNDS. The two patients with OCNDS had global developmental delay, muscle weakness (hypotonia), and seizures. However, their other symptoms were overall different. One patient had aberrant facial and brain structures, short stature, and progressive muscle weakness that eventually led to respiratory failure. Afterwards, this patient always required a ventilator and a wheelchair. The second patient had more frequent seizures that lead to brain death at 1 year and 7 months of age, even though they had no obvious facial or brain structural issues like the first patient. These patients were found to have two different mutations in the CSNK2A1 gene. The differences in symptoms between these patients may be in part due to these different mutations, although most symptoms of OCNDS do not correlate well with any specific mutation patients have displayed. The first patient had the most common OCNDS mutation currently known, termed “p.K198R”, whereas the second patient with severe seizures had a mutation known as “p.R191*.” When comparing these patients with previously published reports of OCNDS, every OCNDS patient was found to have developmental delay (28/28), while many had intellectual disabilities (26/28) and hypotonia (muscle weakness – 20/28). These traits were often, but not always, accompanied by issues moving, autistic traits, sleep problems, short stature, gastrointestinal issues, cardiac abnormalities, and seizures, among other symptoms. To date, the condition of the second patient with recurrent seizures who passed away at the age of 1 year and 7 months is the most severe OCNDS case reported, although both patients experienced severe symptoms.

Authors: Davide Colavito, Elda Del Giudice, Chiara Ceccato, Maurizio Dalle-Carbonare, Alberta Leon, Agnese Suppiei Publication Date: March 22, 2018 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/s10038-018-0434-y Research Explained Summary: This article reports on a patient with OCNDS whose first presentation was isolated retinal dystrophy, or progressive dysfunction of the retina and therefore, vision. This is the first instance where vision problems were the primary symptom that brought the patient into the clinic and resulted in an OCNDS diagnosis. At birth, the patient showed no evidence of any disabilities that might have indicated OCNDS or other disorders. However, at four months of age, the patient was admitted to a hospital for suspected low vision and infantile nystagmus, a condition where the patient’s eyes rapidly and involuntarily shake in a horizontal or vertical direction. After doctors examined the individual, a diagnosis of isolated Leber’s congenital amaurosis was reached, which is a family of conditions that include varying degrees of severe vision loss at an early age. The doctors also initiated genetic testing to determine the cause, as this disease is primarily a genetic disorder. By 10 months of age, the patient was displaying symptoms more typical of OCNDS, including poor muscle tone (hypotonia), poor muscle control (ataxia), sleep disturbances, and general failure to reach psychological and motor milestones expected for normal development. Genetic results showed a c.1061-1G>C mutation in CSNK2A1, the gene whose mutation causes OCNDS. This was the first report of an OCNDS patient with retinal dystrophy. This case report highlights that ocular/retinal symptoms of OCNDs should be monitored and might be more common than previously thought.

Authors: H L Duan, J Peng, N Pang, S M Chen, J Xiong, S Q Guang, F Yin Publication Date: May 2019 Link to article: https://pubmed.ncbi.nlm.nih.gov/31060130/ Research Explained Summary: This publication is a case report of an individual with OCNDS that has the c.524A>G (p.D175G) variant in the CSNK2A1 gene and is the first report of OCNDS in the mainland of China. The patient was a 1 year and 8-month-old boy with symptoms that included microcephalus (small head), broad nasal bridge, micrognathia (small lower jaw), and hypotonia. The authors then summarized the clinical findings of OCNDS at the time of publication, which included mostly individuals with missense changes (a genetic alteration that occurs when a single base pair in DNA is substituted, resulting in a different amino acid being incorporated into a protein) in the CSNK2A1 gene, with the K198R change being the most common.

Authors: Ruohao Wu, Wenting Tang, Liyang Liang, Xiaojuan Li, Nengtai Ouyang, Zhe Meng Publication Date: June 10, 2020 Link to article: https://rs.yiigle.com/cmaid/1202672 Research Explained Summary: This publication is a case study on an individual with OCNDS that has the c.149A>G (p. Tyr50Cys) variant in the CSNK2A1 gene. At the time of publication, this variant had not yet been reported. Research showed that this specific part of the gene has been highly conserved across species and that this DNA change was predicted change of the original spatial structure of CK2α protein and the loss of the original protein function.

Authors: Priya Ranganath, Prajnya Ranganath, V S Vineeth, Ashwin Dalal, Siddaramappa J Patil Publication Date: 2021 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Link to article: https://irp.cdn-website.com/5b9bc46f/files/uploaded/report_of_an_asian_indian_patient_with_okur_chung.12.pdf Research Explained Summary: This publication is a case report of a 6-year-old female with OCNDS that is of Asian-Indian origin. She presented with symptoms not previously reported for individuals with the p.Arg47Gln (R47Q) variant in the CSNK2A1 gene including a frontal upsweep with unusual patterning of scalp hairs, breath-holding spells, and talipes equinovarus (club foot). The authors noted that 3 other individuals with the same genetic variant also had facial dysmorphology including hypertelorism (abnormally increased distance between the eyes), arched eyebrows, low-set ears, and retrognathia (abnormal posterior positioning of the jaw). By publishing this report, the authors expanded knowledge about the symptom presentation across different ethnicities and helps define the presentation of individuals with the specific R47Q variant.

Authors: Raja Brauner, Joelle Bignon-Topalovic, Anu Bashamboo, Ken McElreavey Publication Date: December 14, 2023 Research Explained By: Gabrielle Rushing, PhD, Science Program Director Link to Paper: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0292664 Research Explained 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: Hossein Jafari Khamirani, Sina Zoghi, Ali Motealleh, Mehdi Dianatpour, Seyed Mohammad Bagher Tabei, Sanaz Mohammadi, Seyed Alireza Dastgheib Publication Date: March 31, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9801326/ Research Explained Summary: This case report presents an OCNDS patient who displayed regular seizures, an atypical characteristic for those with OCNDS. The patient presented to the clinic at age 8 due to cognitive, motor, and language developmental delays. At this time, the parents reported severe sleep issues and several episodeclinics of two different forms of seizures, known as myotonic and atonic. These seizures manifest differently: myotonic seizures are characterized by twitching and jerking of the arms and legs, whereas atonic seizures are characterized by a loss of muscle control and/or tension. Other OCNDS symptoms included behavioral issues, autism spectrum disorder, short stature, and muscle weakness (hypotonia). She also displayed poor dental development, although this had not yet been associated with OCNDS. Previously, the patient had been diagnosed with a urea cycle disorder, which causes toxic substances normally excreted through urination to build up in the bloodstream. As a result of this, genetic testing was performed revealing a mutation in the CSNK2A1 gene causative of OCNDS. When later tested again to confirm the urea cycle disorder, the test came back normal. She was being treated for this disorder but discontinued the treatment upon this finding. The authors also reviewed all 33 previously reported OCNDS cases, ranking the relevance of specific symptoms. Developmental delay was reported in all cases, although with great variability in severity. Most patients displayed speech delays, intellectual disability, and dysmorphic facial features. Only 9/31 patients included in this portion of the review were determined to have had seizures, and this patient is the only to have been reported to have two different kinds of seizures. This report displays the great variability present between OCNDS patients.

 Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review Authors: Ruo-Hao Wu, Wen-ting Tang, Kun-yin Qiu, Xiao-juan Li, Dan-xia Tang, Zhe Meng, Zhan-wen He Publication Date: May 26, 2021 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161887/ Research Explained Summary: This case report profiles two new OCNDS patients, then expands to broadly review the literature of all reported OCNDS patients to identify potential correlations between each patient’s specific genetic mutations and any symptoms they experience. The first patient arrived at the clinic at age 3 with severe growth retardation and recurrent febrile seizures . Her development in terms of movement and speaking occurred at a normal pace, but she had her first febrile seizure at nine months of age, experiencing a total of five episodes. All the seizures went away on their own and didn’t require treatment. During her initial consultation, other reported abnormalities included a smaller than usual pituitary gland (a gland which regulates most hormones in the body), and mild immunodeficiency. The second patient arrived at the clinic at age 2, also with major growth delay. This patient’s developmental milestones were severely delayed – she could not yet sit, stand, or speak. However, unlike the first patient, she had a perfectly functioning immune system. Genetic testing was performed on both patients, finding mutations in the CSNK2A1 gene. Each patient had a different mutation, with the first patient having p.H160R, while the second had p.R80C. Both mutations were predicted to be the major cause of their symptoms. A full search of the OCNDS literature revealed 35 patients with detailed workups. The authors tried to link specific mutations found in CSNK2A1 to specific manifestations of OCNDS. The only connection they were able to find was mutations in a specific domain of the CSNK2A1 gene known as the “ATP/GTP binding-loop" were more likely to lead to multi-organ abnormalities, although these symptoms weren’t necessarily more severe. This study further illustrates the wide variety of manifestations of OCNDS and confirms the lack of a strong correlation between what mutation a patient has with their symptoms.

Authors: Shanshan Xu, Jinzhun Wu, Lingli Lu, and Jia Song. Publication Date: August 3, 2020 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-01096-w Research Explained Summary: This case report describes the co-occurrence of two genetic diseases in one patient, including both OCNDS and tricho-rhino-phalangeal syndrome (TRPS). It also follows the clinical analysis of both parents of the patient to determine the origins of these two rare diseases. The patient first presented to a pediatric endocrinology clinic at almost 7 years old with short stature and developmental delay. Upon presentation, he displayed sparse scalp hair, short stature, and severe intellectual disability, although many blood tests for various physiological variables were normal otherwise. Prior to this, he suffered from developmental delays including walking for the first time and speaking at 4 years of age. He started school at 6 years old but couldn’t communicate with the other children. Genetic testing revealed two mutations that could be disease causing, one in the CSNK2A1 gene (the K198R mutation, the most common in OCNDS), and the TRPS1 gene. The patient’s father has a mild intellectual disability and short stature. Upon genetic testing, the father was found to have the same CSNK2A1 gene mutation as the patient, indicating that the patient inherited it from his father. His mother has sparse scalp hair, short stature, and facial features characteristic of TRPS. Via genetic testing, the mother was found to have the same mutation as the patient in the TRPS1 gene, indicating that the patient inherited TRPS from his mother. Both TRPS and OCNDS present variably in individual patients, although both diseases are characterized by short stature – the patient described herein was extremely short, likely due to a combination of both diseases. This report is the first to describe OCNDS coinciding with another rare disease.

Authors: Moe Akahira-Azuma, Yoshinori Tsurusaki, Yumi Enomoto, Jun Mitsui, Kenji Kurosawa Publication Date: March 29, 2018 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/hgv201811 Research Explained Summary: This case report described a Japanese male OCNDS patient conceived through in vitro fertilization (IVF) with distinctive features separating them from previously described patients, including specific facial features, a friendly and interactive disposition, and macrocephaly (brain/head larger than is typical). This patient was referred to a clinic at 2 years and 10 months of age for a genetic evaluation. At this time, he was nonverbal and was not walking without support. However, he started walking without support at 3 years old, and said his first meaningful words at the age of 6 years. He started school at 7 years old, which rapidly improved his speech to the point where he could answer simple questions but not express complex thoughts. Genetic testing was performed, and a mutation (specifically c.593A>G or p.K198R) in the CSNK2A1 gene was found, causative of OCNDS. The authors compared their patient’s specific symptoms with those found in other neurodevelopmental disorders further indicating the variety of symptoms OCNDS patients might display also appear in other disorders. Pop-up definition: In vitro fertilization (IVF) is a medical procedure that helps some people have babies when they have difficulty doing so naturally. Instead of the baby forming inside the mother's body, like in a natural pregnancy, IVF happens outside the body. [BC1] Here's how it works: Eggs are taken from a woman's ovaries and sperm from a man, and they are combined in a lab dish. When the egg and sperm meet and create an embryo, the doctors put that embryo back into the woman's uterus. If everything goes well, the embryo can grow into a baby inside the mother, just like a regular pregnancy.

Authors: Ceris I. Owen, Ramsay Bowden, Michael J. Parker, Jo Patterson, Joan Patterson, Sue Price, Ajoy Sarkar, Bruce Castle, Charulatha Deshpande, Miranda Splitt, Neeti Ghali, John Dean, Andrew J. Green, Charlene Crosby, Deciphering Developmental Disorders Study, and Katrina Tatton-Brown. Publication Date: December 16th, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38610 Research Explained Summary: Patients with a developmental disorder identified by the Deciphering Developmental Disorders Study at the Wellcome Trust Sanger Institute were genetically sequenced, and 11 were identified to have mutations in the CSNK2A1 gene, causative of OCNDS. Eight distinct mutations were found in these 11 patients, which were not found in the general population, the rest of their developmental disorder cohort, or the parents of the individual children. This indicates that these mutations are de novo, meaning that these mutations weren’t inherited from the child’s parents, but instead occur only in the children. Clinical features were analyzed, with the most frequently reported being intellectual disability at varying levels. Overall, the average amount of time it took for patients to start sitting without help, walking, or speaking were 11.5 months, 30.5 months, and 44 months respectively, which is significantly delayed from typical development. Other commonly observed manifestations included muscle weakness (hypotonia), behavioral issues, swallowing difficulties, short stature, small head/brain size (microcephaly) and heart defects. Although previous studies have reported characteristic facial features, this study indicated that while there were some recurrent features, these were not significantly indicative of OCNDS. Together with previous work, this study increases both the number of known OCNDS cases and validates symptoms found in previous cohorts and individuals. Particularly, this study indicates that cardiac dysfunction should be evaluated in OCNDS patients, a trait which hadn’t been seen before, further highlighting the differences across individuals with OCNDS.

This study reveals eight new cases of OCNDS, highlighting symptoms & genetic insights. Support our mission for affected individuals worldwide.

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 Explained 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.

Learn about a rapid method for evaluating CK2 activity & interactions in E. coli, aiding research on Okur-Chung Neurodevelopmental Syndrome.

Authors: Deciphering Developmental Disorders Study Group Publication Date: January 25, 2017 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/nature21062 Research Explained Summary: This study collected genetic data from 8,361 individuals with neurodevelopmental disorders and sought to determine potential genes where mutations might lead to specific diseases, some previously described and others unknown. Because most individuals in this cohort were the only individuals in their family that had a neurodevelopmental disorder, genetic analyses of this cohort were powered to identify genes whose de novo mutation, or mutations not inherited from either parent, led to disease. Through this analysis, 14 genes were identified as potentially disease causing through their de novo mutation. Among these genes was CSNK2A1, which we now know is causative of OCNDS. 7 individuals with mutations in this gene were identified within this cohort. At the time, OCNDS had only recently been discovered within a small 5 patient cohort – this study found OCNDS among a much larger cohort and further helped characterize the disease.

Authors: Prasida Unni, Jack Friend, Janice Weinberg, Bolkan Okur, Jennifer Hochscherf, Isabel Dominguez Publication Date: October 13, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.frontiersin.org/articles/10.3389/fmolb.2022.851547/full Research Explained Summary: This paper leverages computational modeling to investigate the functional consequences of mutations in the CSNK2A1 and CSNK2B genes on the molecular level. Mutations in these genes lead to OCNDS and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) respectively. They are analyzed together in this paper due to the relatively similar symptoms presented by patients with these diseases and the relatedness of the proteins that are encoded by their corresponding genes. Genes are the molecular blueprint for proteins, which perform molecular functions required for life. The CSNK2A1 and CSNK2B genes encode the proteins CK2α and CK2β respectively. These proteins bind to each other and create a larger complex of proteins known simply as CK2. CK2 is an enzyme, meaning that it causes chemical reactions in a cell, potentially affecting many other proteins – CK2α performs these chemical reactions, while CK2β helps regulate the function of CK2 overall. In this paper, all currently known OCNDS and POBINDS causing mutations were identified and tested. Overall, 68 mutations in the CSNK2A1 gene were examined as potentially causing OCNDS. 12 total locations in the CSNK2A1 gene were found to be recurrently mutated, indicating that these sites are important in development, although there were 45 total mutation sites found. Most of these mutations were clustered closely together on the gene, indicating that the regions they are found in are important to the CSNK2A1 gene and CK2α protein function. These regions are known as the Gly-rich-loop and P+1 loop, which are critical for the enzymatic function of CK2α. The authors tried to predict the specific molecular alterations that CSNK2A1 mutations would have on CK2 protein function using computational algorithms. First, they used computational programs to predict which mutations lead to changes in CK2 enzymatic activity. Afterwards, they compared programs which attempted to determine which mutations lead to greater changes in the overall shape and structure of the CK2 protein. The authors identified mutations in specific domains of the CK2 protein and how they might affect the protein’s function and structure based on the best algorithms identified. Broadly, this study surveys all CSNK2A1 mutations known to date in depth and computationally profiled them on the genetic and protein level to determine specifically how each mutation might impact CK2 function. More knowledge in this area may lead to patient specific treatment approaches and potentially link distinct mutations to specific symptoms.

Authors: Danielle Caefer, Nhat Phan, Jennifer Liddle, Jeremy Balsbaugh, Joseph O’Shea, Anastasios Tzingounis, Daniel Schwartz Publication Date: April 19, 2022 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.frontiersin.org/articles/10.3389/fmolb.2022.850661/full Research Explained Summary: In this article, the researchers deeply characterized the effects of a mutation in the CSNK2A1 gene known as p.K198R. This mutation is the most prevalent mutation found in OCNDS to date. The CSNK2A1 gene encodes a component of the protein known as CK2, an enzyme that causes chemical reactions, generally acting on other proteins in what is known as a “signaling cascade” to modify their ability to perform subsequent functions such as cell growth. To act on its target proteins, CK2 must recognize these proteins. Proteins are comprised of subunits known as amino acids, and a specific string of amino acids in a row can be recognized by other proteins as sites for binding – this is how CK2 knows which proteins to modify. However, the authors of this paper found that the K198R mutation in CSNK2A1 changes the ability of CK2 to bind to sites on specific proteins that it normally acts on, instead biasing CK2 towards new binding sites on different proteins. The researchers then looked for proteins that the K198R mutant CK2 would act on but that the normal CK2 protein wouldn’t act on, indicating potential differences that could be leading to the symptoms seen in OCNDS. Previously, it was thought that this mutation generally decreased CK2 activity instead of changing what downstream proteins it targeted. Together, these results help inform the growing body of research regarding what the molecular function of common OCNDS mutations are so that eventually these differences can be targeted therapeutically.

Authors: Michelle Kowanda, Rebecca Sheedy Smith, Jamie Lundy, Catherine Kentros, Elisheva Kleinman, Lauren Kasparson Walsh, Gerhard Schratt, Cora M. Taylor, Wendy K. Chung Publication Date: April 8, 2024 Research Explained By: Gabrielle Rushing , PhD, Science Program Director Research Simplified Summary: This research paper focuses on the reclassification of genetic variants in neurodevelopmental conditions. Variants are changes in the letters of our DNA that can affect our health – you can think of a variant like a misspelled work in the ‘DNA instruction book’. In some cases, the classification of these variants as either harmful (e.g., pathogenic/likely pathogenic) or benign can change over time as new evidence emerges. Sometimes variants are classified as ‘variants of uncertain significance’ or ‘VUS’ meaning that scientists need more information to decide how to classify them. This study looked at the reclassification of VUS in a large group of rare diseases that affect brain development enrolled in Simons Searchlight, including OCNDS. The researchers found that about 20% of the variants were reclassified, with some being upgraded to a more harmful classification and others being downgraded to a less harmful classification. They interpreted classification using existing published research, analyzing DNA from family members, and used the variant reinterpretation guidelines tool from the American College of Medical Genetics and Genomics. The study found that certain genes, such as SCN2A, SLC6A1, and STXBP1, were more likely to have their variants reclassified. For the CSNK2A1 gene, the authors found 13 individuals with a VUS in Simons Searchlight. Out of these 13, 6 were reclassified as pathogenic or likely pathogenic. Regular reevaluation of genetic variants is important because it can affect clinical care and help researchers better understand these conditions. The study also highlighted the need for more diverse representation in genetic databases to ensure equitable healthcare for all populations.

Explore the CK2αLys198Arg mutation's impact on substrate specificity. Join us in finding a cure for Okur-Chung Neurodevelopmental Syndrome.

Authors: Christian Borgo, Claudio D’Amore, Stefania Sarno, Mauro Salvi, Maria Ruzzene Publication Date: May 17, 2021 Research Explained By: Brad Davidson, CSNK2A1 Foundation Science Communication Intern Link to article: https://www.nature.com/articles/s41392-021-00567-7 Research Explained Summary: In this review article, the authors summarize all research conducted to date on the protein CK2 (Casein Kinase 2), an aggregate of multiple proteins that form a complex including two copies each of CK2α and CK2β, and how it relates to various human diseases. CK2 is an enzyme, meaning that it causes chemical reactions. Its two sub-components perform different functions – CK2α is the catalytic domain that performs the reaction, while CK2β is a regulatory domain that controls when the reaction happens. Unlike many enzymes that perform chemical reactions within a cell, CK2 does not need to be activated by another protein to perform its function. Generally, CK2 acts on other enzymes that are performing functions such as cell survival, growth, and migration among other functions, further increasing their ability to stimulate cells to perform these actions. CK2 was first implicated in human disease in 1995 as a pro-cancer molecule due to its higher-than-expected presence in various cancers. Generally, cancers use their high levels of CK2 to promote cell survival and growth, granting them the ability to continue growing in the face things that usually kill cancers, such as the immune system and therapeutics. Other research groups have implicated roles for CK2 in infections, diabetes, cardiovascular diseases, retinal diseases, and inflammatory diseases. In addition, CK2 has been implicated in various neurodegenerative diseases associated with aging, including Parkinson’s, Alzheimer’s, Huntington’s, and Amyotrophic lateral sclerosis (ALS). Furthermore, CK2 has been implicated in a variety of behavioral neurologic disorders including Autism, ADHD, Schizophrenia, Major Depressive Disorder, and most relevant to the CSNK2A1 Foundation, OCNDS. Mutations in the CSNK2A1 gene, which encodes the CK2α subunit of CK2, cause OCNDS. OCNDS is a disease that manifests differently across individuals, but generally leads to symptoms including but not limited to developmental delays, muscular weakness, slow growth, and epilepsy. A similar disorder known as POBINDS caused by mutations in the CSNK2B gene that encodes CK2β has also recently been discovered, with patients displaying similar symptoms to OCNDS but with greater risk of seizure. In terms of treatment for these various CK2-related diseases, there are multiple CK2 inhibitors currently in clinical trials as anti-cancer drugs. The mechanism of action for CK2 in OCNDS is still unclear, meaning that we don’t know if a CK2 inhibitor would be a promising candidate treatment or if CK2 needs to be targeted in a different way.

Authors: Volkan Okur and Wendy Chung Publication Date: June 9, 2022 Research Explained By: Gabrielle Rushing, PhD, CSNK2A1 Foundation Science Program Director and Jennifer Sills, CSNK2A1 Foundation Founder and President Link to article: https://www.ncbi.nlm.nih.gov/books/NBK581083/ Research Explained Summary: Please visit our simplified version of the GeneReview on our Care Recommendations page here.

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Authors: Abdelhalim Loukil, Chloe Barrington, and Sarah C. Goetz Research Explained By: Sarah C. Goetz. PhD, Abdelhalim Loukil. PhD Link to Paper: A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability | PNAS 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.