Research Explained: Okur-Chung neurodevelopmental syndrome: Implications for phenotype and genotype expansion (2024)

Link to Paper: https://doi.org/10.1002/mgg3.2398

Authors: Haitian Nan, Min Chu, Jing Zhang, Deming Jiang, Yihao Wang and Liyong Wu

Research Explained By: Dr. Jennifer Hochscherf

Research Explained Summary:

In this clinical report, the authors describe a novel variant in the CSNK2A1 gene in an OCNDS family. The 31-year-old patient showed abnormal eating habits (a strong predilection for sweets and sugary beverages), recurrent seizures, language impairment and limb weakness. Her neurodevelopment was within the normal range. She experienced her first seizure at the age of 29 and subsequently had recurrent seizure episodes. Further symptoms included involuntary facial twitching, chewing coordination issues, memory decline, visual and auditory hallucinations and daily episodes of limb rigidity and spasms.

Whole Exome Sequencing (WES) was conducted involving the patient, mother, and father. This technique revealed a mutation in the CSNK2A1 gene that was passed on from mother to daughter. The mother exhibited no significant developmental impairments nor intellectual disability but possessed a susceptibility to infections. The mutation in the CSNK2A1 gene that was identified in the patient and her mother is the duplication of the base thymine at position 967 of the coding sequence of the CSNK2A1 gene.

A mutation that adds a new base or deletes a base causes a shift in the reading frame, which is called a frame shift mutation. This leads to completely different building blocks being lined up than actually intended in the construction plan after the mutation site. This often leads to a stop codon, which is the sign to end the linking of building blocks. The cell owns a quality control mechanism that recognizes the mRNAs that harbor such premature stop codons and degrades them to prevent the production of a shortened protein, called nonsense-mediated decay.

The mRNA with the frame shift mutation could not be detected in the study, which indicates that the mRNA is degraded and that the defective CK2alpha protein is not produced. The CSNK2A1 variant is therefore called a “null variant” since no protein product is made. There are always two copies of the CSNK2A1 gene in the cell, one from the father and one from the mother. Hence, there is one copy with the correct sequence in each of the patient's cells, which in this family comes from the father. The study found that the total mRNA transcribed from the CSNK2A1 gene was reduced by around 50% compared to healthy individuals. This suggests that the disease mechanism is due to the presence of less CK2a as compared to individuals without OCNDS.

Many CSNK2A1 variants that have been identified in OCNDS patients carry missense mutations. This means that only one building block of the protein is replaced because of the mutation and the protein continues to be produced although its function is altered. Compared to patients with this type of mutation, the patient presented in the clinical report and her mother have significantly milder symptoms. Other patients with CSNK2A1 null variants show a significantly lower frequency of symptoms, such as speech deficits, dysmorphic facial features, or intellectual disability.

Thus, this study offers insights into the spectrum of clinical manifestations associated with OCNDS and sheds light on the relationship between the mutation at the DNA level and the clinical presentation. Specifically, it highlights that individuals with null variants in the CSNK2A1 present with a milder clinical presentation than individuals with missense variants.

Additional Scientific Background for this paper:

The CSNK2A1 gene is the blueprint for the CK2alpha protein and determines the sequence in which various building blocks, so-called amino acids, are linked to form a long chain. This blueprint is written down in the DNA with four different bases (cytosine [C], guanine [G], adenine [A] and thymine [T]) like letters in a book. Three consecutive bases, known as a codon, contain the information which building block is to be incorporated. To learn more about codons, visit this link .

Between the blueprint on the DNA and the actual assembly of the protein from the individual building blocks, there is another important step: The blueprint is transcribed into a messenger RNA (mRNA). Certain modifications ensure that it ultimately only contains the information for building the protein -like extracting the essential chapters of the construction manual.