|
| Findings | | References |
|
| Humans |
|
| SCN1A | SCN1A mutations explain the majority of Dravet syndrome | Claes et al. [162]; Ohmori et al. [163] |
| Sugawara et al. [164]; Orrico et al. [165] |
| Escayg and Goldin et al. [166] |
| SCN1A mutations display phenotypic heterogeneity: GEFS, febrile seizures, cognitive impairment | Escayg et al. [167, 168] |
| Fujiwara et al. [169]; Osaka et al. [170] |
| Zucca et al. [171]; Orrico et al. [165] |
| Variants in other channels modify the phenotype of SCN1A: SCN8A | Martin et al. [172] |
| CACNB4 | Ohmori et al. [173] |
| SCN1B | SCN1B mutations cause GEFS | Wallace et al. [174] |
| ARX | ARX mutations cause various phenotypes including infantile spasms | Shoubridge et al. [175] |
| CDKL5 | CDKL5 mutations cause early epileptic encephalopathies | Kalscheuer et al. [176]; Weaving et al. 2004 [177] |
| Scala et al. [178]; Archer et al. [179] |
| Cordova-Fletes et al. [180]; Mei et al. [181] |
| Melani et al. [182] |
| MECP2 | MECP2 mutations explain most cases of Rett syndrome. These patients often display seizures. | Amir et al. [147]; Buyse et al. [148] |
| GABRG2 | Mutations in the gamma2 subunit of the GABAAR cause childhood absence epilepsy ± febrile seizure | Wallace et al. [174]; Kananura et al. [183] |
| Truncation of GABRG2 causes generalised epilepsy with febrile seizure (GEFS) | Harkin et al. [184] |
| GABRA1 | Mutations in the alpha1 subunit of the GABAAR cause juvenile myoclonic epilepsy | Cossette et al. [185] |
| Mutations in the alpha1 subunit of the GABAAR can also cause childhood absence epilepsy | Maljevic et al. [186] |
| CACNA1A | Polymorphisms associated with generalised epilepsy syndromes | Chioza et al. [187] |
| Mutations in CACNA1A can cause ataxia with generalized seizures | Jouvenceau et al. [188]; Imbrici et al. [189] |
| CACNB4 | Mutations in CACNB4 cause episodic ataxia with generalized seizures | Escayg et al. [190] |
| CACNA1H | Mutations in T-type calcium channel Cav3.2 cause childhood absence epilepsy | Khosravani et al. [191] |
| Nkx2.1 | Nkx2.1 haploinsufficiency leads to the “brain-lung-thyroid syndrome” | Carre et al. [192] |
| variable phenotype: severe respiratory distress at birth, mild-moderate hypothyroidism, chorea | Guillot et al. [193] |
| Some patients present benign hereditary chorea, occasionally with cognitive impairment and seizures | Kleiner-Fisman et al. [194, 195] |
| Dlx5/6 | Dlx5/6 mutations result in craniofacial and limb anomalies: ectodermal dysplasia | Morasso et al. [196]; Lo Lacono et al. [197] |
| Sox 6 | 1 patient described with heterozygote Sox6 mutation: craniosynostosis and facial dysmorphisms. | Tagariello et al. [198] |
|
| Mice |
|
| Scn1a | Scn1a (Nav1.1) expressed in most neuronal populations | Yu et al. [199] |
| Scn1a+/−and Scn1a−/−mice develop spontaneous seizures and die prematurely | Yu et al. [199] |
| sodium currents are specific to GABAergic interneurons in Scn1a+/− and Scn1a−/− | Yu et al. [199] |
| Selective loss of Scn1a in interneurons recapitulates seizure disorder | Martin et al. [200] |
| Arx | Role in neuronal proliferation and migration | Fricourt et al. [201, 202] |
| Specific requirement of Arx for interneuron migration | Friocourt and Parnavelas [203]; Poirier et al. [204] |
| Arx is a downstream target of Dlx1 | Colasante et al. [205] |
| Arx(GCG)10+7 mice display seizures including spasms and no. of CB and NPY interneurons | Price et al. [206] |
| Selective loss of Arx in interneurons recapitulates the seizure disorder | Marsh et al. [207] |
| Cdkl5 | Cdkl5 is coexpressed with Mecp2 in cortical neurons and can phosphorylate Mecp2 | Mari et al. [208], Bertani et al. [209] |
| MecP2 | Mecp2 broadly represses gene expression by binding methylated CPG islands | Nan et al. [210, 211] |
| Cacna1a | Cacna1atg/tg tottering mutant displays ataxia and absence seizures | Noebels et al. [212]; Fletcher et al. [213] |
| Gain of thalamic T-type currents cause enhanced rebound bursting of TC cells in Cacna1atg/tg, Cacna1aln/ln | Zhang et al. [214]; Tsakiridou et al. [215] |
| Interneuron selective ablation of Cacna1a leads to multiple types of generalised seizures incl. absences | Rossignol et al. [63] (abstract) |
| Cacnb4 | Cacnb4lh/lh loss-of-function mutants display spontaneous absence seizures and ataxia | Burgess et al. [216] |
| Thalamic tonic GABAA currents enhance rebound bursting of TC cells in Cacnb4lh/lh | Cope et al. [217] |
| Dlx1/2 | Dlx1−/−Dlx2−/− mice die perinatally and display a failure of IN migration to cortex and olfactory bulb | Anderson et al. [23, 218]; Bulfone et al. [219] |
| Dlx1−/−Dlx2+/− abnormal laminar distribution of IN and simplified morphology | Cobos et al. [220] |
| Dlx1−/− morphological defect and postnatal loss of SST+/CR+ interneurons: spontaneous seizures | Cobos et al. [221] |
| Nkx2.1 | Nkx2.1−/− die perinatally. Nkx2.1 is required for MGE interneuron generation. | Sussel et al. [222] |
| Interneuron specific removal of Nkx2.1 results in misspecification of MGE cells into CGE cells, and seizures | Butt et al. [22] |
| Sox6 | Sox6−/− dies perinatally of craniofacial anomalies | |
| Conditional loss of Sox6 in interneurons results in misplaced/ectopic and immature basket cells (loss PV) | Batista-Brito et al. [28]; Azim et al. [223] |
| Conditional loss of Sox6 in interneurons results in a severe epileptic encephalopathy | Batista-Brito et al. [28] |
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