Generalizált epilepszia hátterében azonosított                     ioncsatorna-génmutáció ritka formája

Till, Ágnes; Szalai, Renáta; Hegyi, Márta; Kövesdi, Erzsébet; Büki, Gergely; Hadzsiev, Kinga; Melegh, Béla

doi:10.1556/650.2019.31404

Cited by 8 publications

(6 citation statements)

References 7 publications

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“…No change in membrane expression, L426P, G551D: ↓ expression and glycosylation. Loss Cl extrusion activity [ 51 , 88 ] V473I IGE [ 89 ] S748del, R857L CT EIMFS [ 87 , 88 ] R1048W ASD [ 90 ] R952H, R1049C ASD, SCZ, IGE Impaired transport activity [ 85 , 90 ] R952H Febrile seizures ↓ Cl extrusion. Impaired ability to form dendritic spines.…”

Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

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Cation-coupled chloride cotransporters (CCCs) modulate the transport of sodium and/or potassium cations coupled with chloride anions across the cell membrane. CCCs thus help regulate intracellular ionic concentration and consequent cell volume homeostasis. This has been largely exploited in the past to develop diuretic drugs that act on CCCs expressed in the kidney. However, a growing wealth of evidence has demonstrated that CCCs are also critically involved in a great variety of other pathologies, motivating most recent drug discovery programs targeting CCCs. Here, we examine the structure-function relationship of CCCs. By linking recent high-resolution cryogenic electron microscopy (cryo-EM) data with older biochemical/functional studies on CCCs, we discuss the mechanistic insights and opportunities to design selective CCC modulators to treat diverse pathologies. Cation-coupled chloride cotransporters (CCCs): from structure to function and modulationCCCs are proteins (~130 kDa) of the subfamily of solute carrier transporters (see Glossary) 12 (SLC12) that modulate transport of sodium and/or potassium cations (Na + , K + ) and chloride anions (Cl -) across the cell membrane (Figure 1A). In humans, there are seven known electroneutral CCCs: the Na + -Clcotransporter NCC, the Na + -K + -Clcotransporters NKCC1 and NKCC2, and the K + -Clcotransporters KCC1, KCC2, KCC3, and KCC4 (Figure 1B) [1]. NCC and NKCC2 are expressed predominantly in the kidney [2]. NKCC1, KCC1, KCC3, and KCC4 are expressed throughout the body. KCC2 is expressed specifically in neurons [3]. CCCs are involved in physiological processes, including salt absorption and secretion, cell volume regulation, and intracellular Clconcentration setting [1,4]. As such, CCCs are primarily implicated in blood pressure regulation, cardiovascular and brain physiopathology, and diuresis, and are also associated with hearing and tumoral diseases (Figure 1C,D). Structure-function relationshipsCCCs mainly form homodimers, although multimeric states have been described in functional assays for N(K)CCs and KCCs [5][6][7]. Monomers for each of the CCC family members are characterized by a well-conserved transmembrane (TM) domain formed by 12 TM helices, one N-glycosylated extracellular (EC) domain, and, on the cytosolic side, the amino-terminal (NT) and the large carboxy-terminal (CT) domains (Figure 1A). All SLC12-CCC members share the same TM protein fold of the leucine transporter (LeuT [8], Box 1). The EC domain is characterized by a connecting loop between TM7 and TM8 in Na + -dependent CCCs, whereas Na + -independent CCCs have a longer loop between TM5 and TM6. The NT and EC domains are variable in amino acid length, much shorter than the CT domain, and poorly conserved among the CCC members. The EC domains contain glycosylation sites, whereas the intracellular domains contain phosphorylation sites to modulate CCC function (Figure 1A) [9]. Molecular heterogeneity is also provided by multiple CCC isoforms, generated by alternative splicing and alternative promote...

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Section: Mutations Associated With Human Diseasesmentioning

confidence: 99%

Cation-coupled chloride cotransporters: chemical insights and disease implications

Portioli

Munevar²,

Vivo³

et al. 2021

Trends in Chemistry

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“…In addition to the mRNAs with increased expression mentioned above, which are related to cell differentiation and proliferation, the decreased expression of SLC12A5 aroused our interest. SLC12A5 (encoding the KCC2 protein) acts to stabilize nerve cell potential, and its reduced expression correlates with the development of epilepsy ( 34 – 39 ). Consistent with our findings, Yang and Gao et al found that the expression of SLC12A5 in patients with shorter survival time was significantly lower than that in patients with longer survival ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

A prognostic estimation model based on mRNA-sequence data for patients with oligodendroglioma

et al. 2022

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BackgroundThe diagnosis of oligodendroglioma based on the latest World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS 5) criteria requires the codeletion of chromosome arms 1p and 19q and isocitrate dehydrogenase gene (IDH) mutation (mut). Previously identified prognostic indicators may not be completely suitable for patients with oligodendroglioma based on the new diagnostic criteria. To find potential prognostic indicators for oligodendroglioma, we analyzed the expression of mRNAs of oligodendrogliomas in Chinese Glioma Genome Atlas (CGGA).MethodsWe collected 165 CGGA oligodendroglioma mRNA-sequence datasets and divided them into two cohorts. Patients in the two cohorts were further classified into long-survival and short-survival subgroups. The most predictive mRNAs were filtered out of differentially expressed mRNAs (DE mRNAs) between long-survival and short-survival patients in the training cohort by least absolute shrinkage and selection operator (LASSO), and risk scores of patients were calculated. Univariate and multivariate analyses were performed to screen factors associated with survival and establish the prognostic model. qRT-PCR was used to validate the expression differences of mRNAs.ResultsA total of 88 DE mRNAs were identified between the long-survival and the short-survival groups in the training cohort. Seven RNAs were selected to calculate risk scores. Univariate analysis showed that risk level, age, and primary-or-recurrent status (PRS) type were statistically correlated with survival and were used as factors to establish a prognostic model for patients with oligodendroglioma. The model showed an optimal predictive accuracy with a C-index of 0.912 (95% CI, 0.679–0.981) and harbored a good agreement between the predictions and observations in both training and validation cohorts.ConclusionWe established a prognostic model based on mRNA-sequence data for patients with oligodendroglioma. The predictive ability of this model was validated in a validation cohort, which demonstrated optimal accuracy. The 7 mRNAs included in the model would help predict the prognosis of patients and guide personalized treatment.

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“…This suggests that reduced KCC2 activity may be involved in the mechanisms underlying increased excitability in the brains of epileptic patients. The identification of various KCC2 mutations (encoded by SLC12A5 ) has further highlighted the association between KCC2 dysfunction and the development of epilepsy [ 41 – 46 ]. A summary of the KCC2 mutations discovered in human epilepsy can be found in Table 1 [ 47 ], with their localization shown in Fig.…”

Section: The Role Of Kcc2 In Epileptogenesismentioning

confidence: 99%

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

McMoneagle,

Zhou,

Zhang

et al. 2023

Acta Pharmacol Sin

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Epilepsy is a prevalent neurological disorder characterized by unprovoked seizures. γ-Aminobutyric acid (GABA) serves as the primary fast inhibitory neurotransmitter in the brain, and GABA binding to the GABAA receptor (GABAAR) regulates Cl- and bicarbonate (HCO3-) influx or efflux through the channel pore, leading to GABAergic inhibition or excitation, respectively. The neuron-specific K+-Cl- cotransporter 2 (KCC2) is essential for maintaining a low intracellular Cl- concentration, ensuring GABAAR-mediated inhibition. Impaired KCC2 function results in GABAergic excitation associated with epileptic activity. Loss-of-function mutations and altered expression of KCC2 lead to elevated [Cl-]i and compromised synaptic inhibition, contributing to epilepsy pathogenesis in human patients. KCC2 antagonism studies demonstrate the necessity of limiting neuronal hyperexcitability within the brain, as reduced KCC2 functioning leads to seizure activity. Strategies focusing on direct (enhancing KCC2 activation) and indirect KCC2 modulation (altering KCC2 phosphorylation and transcription) have proven effective in attenuating seizure severity and exhibiting anti-convulsant properties. These findings highlight KCC2 as a promising therapeutic target for treating epilepsy. Recent advances in understanding KCC2 regulatory mechanisms, particularly via signaling pathways such as WNK, PKC, BDNF, and its receptor TrkB, have led to the discovery of novel small molecules that modulate KCC2. Inhibiting WNK kinase or utilizing newly discovered KCC2 agonists has demonstrated KCC2 activation and seizure attenuation in animal models. This review discusses the role of KCC2 in epilepsy and evaluates its potential as a drug target for epilepsy treatment by exploring various strategies to regulate KCC2 activity.

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Generalizált epilepszia hátterében azonosított ioncsatorna-génmutáció ritka formája

Cited by 8 publications

References 7 publications

Cation-coupled chloride cotransporters: chemical insights and disease implications

Cation-coupled chloride cotransporters: chemical insights and disease implications

A prognostic estimation model based on mRNA-sequence data for patients with oligodendroglioma

Neuronal K+-Cl- cotransporter KCC2 as a promising drug target for epilepsy treatment

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