De novo variants in KCNJ3 are associated with early-onset epilepsy
© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:61 |
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| Enthalten in: |
Journal of medical genetics - 61(2024), 4 vom: 21. März, Seite 319-324 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Juan [VerfasserIn] |
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| Links: |
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| Themen: |
Epilepsy |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 25.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1136/jmg-2023-109201 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364553286 |
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| 100 | 1 | |a Li, Juan |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a De novo variants in KCNJ3 are associated with early-onset epilepsy |
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| 520 | |a © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a epilepsy | |
| 650 | 4 | |a genetics | |
| 650 | 7 | |a Potassium Channels |2 NLM | |
| 650 | 7 | |a KCNJ3 protein, human |2 NLM | |
| 650 | 7 | |a G Protein-Coupled Inwardly-Rectifying Potassium Channels |2 NLM | |
| 700 | 1 | |a Mei, Shiyue |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Lily |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Yanmin |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Weiyue |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Lili |e verfasserin |4 aut | |
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