Identification and functional analysis of a novel CSNK2A1 frameshift variant in stillbirth
Nannan Zhang1,2, Miao Han1, Tong Zhao1
1Department of Prenatal Diagnosis, Lianyungang Maternal and Child Health Hospital of Yangzhou University, Lianyungang, China.
Background:
Casein Kinase II Subunit Alpha (CK2α), the catalytic subunit of protein kinase CK2, is encoded by CSNK2A1. This kinase catalyzes substrate phosphorylation and regulates diverse cellular processes including cell cycle progression, apoptosis, and transcription. CSNK2A1 is associated with Okur-Chung Neurodevelopmental Syndrome (OCNS, OMIM: 617062). Although CSNK2A1 functional deficiency is implicated in impaired embryonic development, prenatal case reports remain scarce.
Methods:
Clinical data and fetal umbilical cord blood samples were collected. Whole-genome sequence (WGS) was used for potential pathogenic variants identification, followed by Sanger sequencing to validate the variant. Bioinformatic tools were employed to predict the 3D structure of the variant. Wild-type and mutant CSNK2A1 overexpression plasmids were constructed to investigate the functional consequences of the variant.
Result:
A 33-year-old pregnant woman without adverse obstetric history. At 34+4 weeks, ultrasound showed an intracranial abnormal echoes, multiple cardiovascular anomalies, and stillbirth had occurred at 35 weeks. WGS identified a novel frameshift mutation c.1020_1021delAG (p.Gly342Glnfs*57) in the CSNK2A1 gene. Bioinformatics analysis indicated structural modification in mutant proteins. In vitro kinase assays showed that the variant did not impair kinase activity. Quantitative analysis demonstrated significantly elevated mutant mRNA levels but reduced protein expression compared to wild-type. Elevated ubiquitination in mutants potentially explains diminished CSNK2A1 protein abundance.
Conclusion:
We report a novel CSNK2A1 frameshift mutation that significantly reduces protein expression and impairs gene function. These findings expand our understanding of CSNK2A1's genetic diversity and underscore the importance of comprehensive functional analyses to achieve accurate diagnosis. This study facilitates prenatal diagnosis of CSNK2A1-related disorders and informs clinical decision-making for carriers.
Insights
A novel frameshift mutation in the CSNK2A1 gene was identified in a stillborn fetus, leading to reduced protein expression and impaired function. This finding aids in prenatal diagnosis of CSNK2A1-related disorders.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Casein Kinase II Subunit Alpha (CK2α), encoded by CSNK2A1, regulates crucial cellular processes.
- CSNK2A1 mutations are linked to Okur-Chung Neurodevelopmental Syndrome (OCNS).
- Prenatal cases of CSNK2A1 deficiency are rare, despite its role in embryonic development.
Purpose of the Study:
- To investigate a novel CSNK2A1 mutation identified in a prenatal case.
- To determine the functional consequences of the identified mutation.
- To enhance understanding of CSNK2A1-related disorders for improved prenatal diagnosis.
Main Methods:
- Whole-genome sequencing (WGS) for variant identification.
- Sanger sequencing for variant validation.
- Bioinformatic prediction of protein structure and in vitro functional assays (kinase activity, mRNA/protein levels, ubiquitination).
Main Results:
- A novel frameshift mutation (c.1020_1021delAG) in CSNK2A1 was identified in a fetus with structural anomalies and stillbirth.
- The mutation led to significantly elevated mutant mRNA but reduced protein expression.
- While kinase activity was not impaired, elevated ubiquitination suggested a mechanism for reduced protein abundance.
Conclusions:
- A novel CSNK2A1 frameshift mutation significantly reduces protein expression and impairs gene function.
- This study expands the known genetic variations in CSNK2A1 and highlights the need for comprehensive functional analysis.
- Findings facilitate prenatal diagnosis of CSNK2A1-related disorders and support clinical decision-making.
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