A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion
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, pathogen...
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1372662/full |
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| author | Viivi Järvelä Viivi Järvelä Viivi Järvelä Mira Hamze Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Elisa Rahikkala Elisa Rahikkala Elisa Rahikkala Johanna Piispala Mika Kallio Salla M. Kangas Salla M. Kangas Tereza Nickl Tereza Nickl Tereza Nickl Marko Huttula Reetta Hinttala Reetta Hinttala Reetta Hinttala Johanna Uusimaa Johanna Uusimaa Johanna Uusimaa Igor Medina Esa-Ville Immonen Esa-Ville Immonen Esa-Ville Immonen |
| author_facet | Viivi Järvelä Viivi Järvelä Viivi Järvelä Mira Hamze Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Elisa Rahikkala Elisa Rahikkala Elisa Rahikkala Johanna Piispala Mika Kallio Salla M. Kangas Salla M. Kangas Tereza Nickl Tereza Nickl Tereza Nickl Marko Huttula Reetta Hinttala Reetta Hinttala Reetta Hinttala Johanna Uusimaa Johanna Uusimaa Johanna Uusimaa Igor Medina Esa-Ville Immonen Esa-Ville Immonen Esa-Ville Immonen |
| author_sort | Viivi Järvelä |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-24T11:36:38Z |
| format | Article |
| id | doaj.art-c924fe7976664232b84b934d595bc41c |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-24T11:36:38Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-c924fe7976664232b84b934d595bc41c2024-04-10T05:20:23ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-04-011710.3389/fnmol.2024.13726621372662A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusionViivi Järvelä0Viivi Järvelä1Viivi Järvelä2Mira Hamze3Jonna Komulainen-Ebrahim4Jonna Komulainen-Ebrahim5Jonna Komulainen-Ebrahim6Elisa Rahikkala7Elisa Rahikkala8Elisa Rahikkala9Johanna Piispala10Mika Kallio11Salla M. Kangas12Salla M. Kangas13Tereza Nickl14Tereza Nickl15Tereza Nickl16Marko Huttula17Reetta Hinttala18Reetta Hinttala19Reetta Hinttala20Johanna Uusimaa21Johanna Uusimaa22Johanna Uusimaa23Igor Medina24Esa-Ville Immonen25Esa-Ville Immonen26Esa-Ville Immonen27Nano and Molecular Systems Research Unit, University of Oulu, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandINMED, INSERM, Aix-Marseille University, Marseille, FranceResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandDepartment of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandDepartment of Clinical Genetics, Oulu University Hospital, Oulu, FinlandDepartment of Clinical Neurophysiology, Oulu University Hospital, Oulu, FinlandDepartment of Clinical Neurophysiology, Oulu University Hospital, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandLaboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, CzechiaNano and Molecular Systems Research Unit, University of Oulu, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandBiocenter Oulu, University of Oulu, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandDepartment of Children and Adolescents, Division of Pediatric Neurology, Oulu University Hospital, Oulu, FinlandINMED, INSERM, Aix-Marseille University, Marseille, FranceNano and Molecular Systems Research Unit, University of Oulu, Oulu, FinlandResearch Unit of Clinical Medicine, University of Oulu, Oulu, FinlandMedical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, FinlandThe 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.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1372662/fullSLC12A5GABApotassium-chloride co-transporterchlorideCl−epilepsy |
| spellingShingle | Viivi Järvelä Viivi Järvelä Viivi Järvelä Mira Hamze Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Jonna Komulainen-Ebrahim Elisa Rahikkala Elisa Rahikkala Elisa Rahikkala Johanna Piispala Mika Kallio Salla M. Kangas Salla M. Kangas Tereza Nickl Tereza Nickl Tereza Nickl Marko Huttula Reetta Hinttala Reetta Hinttala Reetta Hinttala Johanna Uusimaa Johanna Uusimaa Johanna Uusimaa Igor Medina Esa-Ville Immonen Esa-Ville Immonen Esa-Ville Immonen A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion Frontiers in Molecular Neuroscience SLC12A5 GABA potassium-chloride co-transporter chloride Cl− epilepsy |
| title | A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion |
| title_full | A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion |
| title_fullStr | A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion |
| title_full_unstemmed | A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion |
| title_short | A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion |
| title_sort | novel pathogenic slc12a5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired kcc2 chloride extrusion |
| topic | SLC12A5 GABA potassium-chloride co-transporter chloride Cl− epilepsy |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1372662/full |
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