A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F24%3A00585854" target="_blank" >RIV/68378050:_____/24:00585854 - isvavai.cz</a>
Result on the web
<a href="https://www.frontiersin.org/articles/10.3389/fnmol.2024.1372662/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fnmol.2024.1372662/full</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3389/fnmol.2024.1372662" target="_blank" >10.3389/fnmol.2024.1372662</a>
Alternative languages
Result language
angličtina
Original language name
A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion
Original language description
The potassium-chloride co-transporter 2, KCC2, is a neuron-specific ion transporter that plays a multifunctional role in neuronal development. In mature neurons, KCC2 maintains a low enough intracellular chloride concentration essential for inhibitory neurotransmission. During recent years, pathogenic variants in the KCC2 encoding gene SLC12A5 affecting the functionality or expression of the transporter protein have been described in several patients with epilepsy of infancy with migrating focal seizures (EIMFS), a devastating early-onset developmental and epileptic encephalopathy. In this study, we identified a novel recessively inherited SLC12A5 c.692G>A, p. (R231H) variant in a patient diagnosed with severe and drug-resistant EIMFS and profound intellectual disability. The functionality of the variant was assessed in vitro by means of gramicidin-perforated patch-clamp experiments and ammonium flux assay, both of which indicated a significant reduction in chloride extrusion. Based on surface immunolabeling, the variant showed a reduction in membrane expression. These findings implicate pathogenicity of the SLC12A5 variant that leads to impaired inhibitory neurotransmission, increasing probability for hyperexcitability and epileptogenesis.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Frontiers in Molecular Neuroscience
ISSN
1662-5099
e-ISSN
1662-5099
Volume of the periodical
17
Issue of the periodical within the volume
Apr
Country of publishing house
CH - SWITZERLAND
Number of pages
16
Pages from-to
1372662
UT code for WoS article
001207196900001
EID of the result in the Scopus database
2-s2.0-85191067049