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Neurogenetics
Original research
De novo variants in KCNJ3 are associated with early-onset epilepsy
  1. Juan Li1,2,3,
  2. Shiyue Mei4,
  3. Xiao Mao5,6,
  4. Lily Wan7,
  5. Hua Wang8,
  6. Bo Xiao1,2,3,
  7. Yanmin Song9,
  8. Weiyue Gu10,
  9. Yan Liu11,
  10. Lili Long1,2,3
  1. 1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China
  2. 2 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
  3. 3 Clinical Research Center for Epileptic Disease of Hunan Province, Central South University, Changsha, Hunan, China
  4. 4 Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China
  5. 5 Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
  6. 6 National Health Commission Key Laboratory for Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
  7. 7 Department of Anatomy & Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
  8. 8 Department of Medical Genetics, Hunan Children's Hospital, Changsha, Hunan, China
  9. 9 Department of Emergency Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
  10. 10 Chigene (Beijing) Translational Medical Research Center Co. Ltd, Beijing, China
  11. 11 Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  1. Correspondence to Dr Lili Long, Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China; longlili1982{at}126.com; Dr Yan Liu, Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; lyan3022{at}163.com

Abstract

Background KCNJ3 encodes a subunit of G-protein-coupled inwardly rectifying potassium channels, which are important for cellular excitability and inhibitory neurotransmission. However, the genetic basis of KCNJ3 in epilepsy has not been determined. This study aimed to identify the pathogenic KCNJ3 variants in patients with epilepsy.

Methods Trio exome sequencing was performed to determine potential variants of epilepsy. Individuals with KCNJ3 variants were recruited for this study. Detailed clinical information and genetic data were obtained and systematically reviewed. Whole-cell patch-clamp recordings were performed to evaluate the functional consequences of the identified variants.

Results Two de novo missense variants (c.998T>C (p.Leu333Ser) and c.938G>A (p. Arg313Gln)) in KCNJ3 were identified in two unrelated families with epilepsy. The variants were absent from the gnomAD database and were assumed to be damaging or probably damaging using multiple bioinformatics tools. They were both located in the C‐terminal domain. The amino acid residues were highly conserved among various species. Clinically, the seizures occurred at a young age and were under control after combined treatment. Electrophysiological analysis revealed that the KCNJ3 Leu333Ser and Arg313Gln variants significantly compromised the current activities and exhibited loss-of-function (LOF) effects.

Conclusion Our findings suggest that de novo LOF variants in KCNJ3 are associated with early-onset epilepsy. Genetic testing of KCNJ3 in patients with epilepsy may serve as a strategy for precision medicine.

  • epilepsy
  • genetics

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2023-109201

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • JL and SM are joint first authors.

    • Contributors LL: Conceptualisation, methodology, writing—review and editing. YL: Conceptualisation, investigation, writing—review and editing. JL: Formal analysis, investigation, writing—original draft. SM: Formal analysis, investigation, writing—original draft. XM: Methodology, resources. LW: Investigation. HW: Writing—review and editing. BX: Writing—review and editing. YS: Investigation. WG: Resources. LL accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish. LL is responsible for the overall content as guarantor.

    • Funding This work was supported by grants from the National Key Research and Development Program of China (2021YFC1005305 and 2019YFC1005100), National Natural Science Foundation of China (82171454 and 82371464), National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Project for Major Diseases of Xiangya Hospital, Central South University (z027001), Key Research and Development Program of Hunan Province (2022SK2042), Natural Science Foundation of Hunan Province Project (2020JJ5914), Innovative Construction Foundation of Hunan Province (2021SK4001), National Natural Science Foundation of China (81701125), Foundation of the Department of Science and Technology of Henan Province (182102310418), and National Population Health Data Center Project (sub-project: SJPT-03-01).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.