A de novo missense mutation in <i><scp>SLC12A5</scp></i> found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

Saito, Takashi; Ishii, Atsushi; Sugai, Kenji; Sasaki, Masayuki; Hirose, Shinichi

doi:10.1111/cge.13049

Cited by 41 publications

(40 citation statements)

References 16 publications

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“…The postnatal development of canonical hyperpolarizing GABAAR currents is a reflection of the progressive decrease of intraneuronal Clthat is caused by the upregulation of KCC2 expression and activity, which do not reach their maximal levels in humans until 20-25 years of age (3). Consistent with this critical role in regulating inhibitory neurotransmission, patients with mutations in SLC12A5 exhibit severe epilepsy that develops after birth, together with severe developmental delay (4)(5)(6). The essential role KCC2 plays in the brain is further exemplified by gene knock-out studies in mice where homozygotes die shortly after birth (7,8).…”

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confidence: 99%

KCC2 is required for the survival of mature neurons but not for their development

Kontou

Cardarelli

et al. 2020

Preprint

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The K+/Clco-transporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl- levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A -aminobutyric acid receptors GABAARs. In accordance with this, compromised KCC2 activity results in seizures but whether such deficits directly contribute to the subsequent changes in neuronal homeostasis and viability that lead to epileptogenesis, remains to be assessed. Here, we have investigated these issues using conditional ablation of SLC12A5 gene expression with AAVs. Decreasing KCC2 expression resulted in the rapid activation of the extrinsic apoptotic pathway, but not the intrinsic pathway, in mature hippocampal neurons, in vitro and in vivo. Intriguingly, direct pharmacological inhibition of KCC2 in mature hippocampal neurons was also sufficient to activate the apoptotic pathway within 10 minutes. Finally, ablating KCC2 expression during neuronal development had no discernable effects on neuronal development, viability and apoptosis. However, KCC2 was essential for the postnatal development of GABAergic inhibition. Collectively, our results demonstrate that correct KCC2 expression and activity play a critical role in neuronal survival. Perturbed KCC2 activity initiates the extrinsic pathway of apoptosis but has a minimal impact on regulating neuronal development. Thus, increasing KCC2 activity may be a useful strategy to limit neuronal death that underlies epiletogenesis.

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confidence: 99%

KCC2 is required for the survival of mature neurons but not for their development

Kontou

Cardarelli

et al. 2020

Preprint

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“…However, activity-induced deficits in synaptic inhibition were reduced, which is sufficient to limit epileptiform activity induced by the potassium channel blocker, 4-aminopyridine [21]. Importantly, a range of mutations and variants in SLC12A5 is now known to confer genetic predispositions to childhood SE [51][52][53][54]. These findings have been reviewed recently by Duy and colleagues [48].…”

Section: Kcc2 As a Therapeutic Target In Epilepsy And Neuropathic Painmentioning

confidence: 99%

The Expanding Therapeutic Potential of Neuronal KCC2

Tang

2020

Cells

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Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

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“…In keeping with its essential role in determining the efficacy of synaptic inhibition, humans with mutations in Kcc2 develop severe epilepsy soon after birth (14)(15)(16). Deficits in Kcc2 activity are also believed to contribute to the development of temporal lobe epilepsy (17,18), in addition to other traumas including ischemia and neuropathic pain (19,20).…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of multi-protein complexes enriched in the K-Cl co-transporter 2 from brain plasma membranes

Smalley

Kontou

Choi

et al. 2020

Preprint

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Kcc2 plays a critical role in determining the efficacy of synaptic inhibition, however, the cellular mechanism neurons use to regulate its membrane trafficking, stability and activity are ill-defined. To address these issues, we used affinity purification to isolate stable multi-protein complexes of Kcc2 from the plasma membrane of murine forebrain. We resolved these using Blue-native polyacrylamide gel electrophoresis (BN-PAGE) coupled to LC-MS/MS. Purified Kcc2 migrated as distinct molecular species of 300, 600 and 800 kDa following BN-PAGE. In excess of 90% coverage of the soluble N and C-termini of Kcc2 was obtained. The 300kDa species largely contained Kcc2, which is consistent with a dimeric quaternary structure for this transporter. Intriguingly, lower levels of Kcc1 were also found in this species suggesting the existence of “mixed” Kcc2/Kcc1 heterodimers. The 600 and 800 kDa species represented stable multi-protein complexes of Kcc2. We identified a set of novel structural, ion transporting and signaling protein interactors, that are present at both excitatory and inhibitory synapses, consistent with the proposed association of Kcc2. These included spectrins, ankyrins, and the IP3 receptor. We also identified interactors more directly associated with phosphorylation; Akap5 and Lmtk3. Finally, we used LC-MS/MS on highly purified endogenous plasma membrane Kcc2 to detect phosphorylation sites. We detected 11 sites with high confidence, including known and novel sites. Collectively our experiments demonstrate that Kcc2 is associated with components of the neuronal cytoskeleton and signaling molecules that may act to regulate transporter membrane trafficking, stability, and activity.

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A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

Cited by 41 publications

References 16 publications

KCC2 is required for the survival of mature neurons but not for their development

KCC2 is required for the survival of mature neurons but not for their development

The Expanding Therapeutic Potential of Neuronal KCC2

Isolation and characterization of multi-protein complexes enriched in the K-Cl co-transporter 2 from brain plasma membranes

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