Nucleus

CytoplasmCytoplasm, perinuclear regionNucleus

Developmental and epileptic encephalopathy 87

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE87 inheritance is autosomal dominant.

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:10449790, PubMed:29961870, PubMed:31032849). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interfaces (By similarity). When activated by GABA, GABAARs selectively allow the flow

Postsynaptic cell membraneCell membraneCytoplasmic vesicle membraneCell projection, dendrite

Developmental and epileptic encephalopathy 78

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE78 is an autosomal dominant form characterized by onset of refractory seizures in the first days or months of life. Clinical features include severe developmental delay, hypotonia, microcephaly, cortical visual impairment and profound intellectual disability. Some patients manifest a less severe phenotype characterized by pharmacoresponsive epilepsy, autism spectrum disorder and moderate intellectual disability.

Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala) (PubMed:27622773, PubMed:27911835, PubMed:28493438, PubMed:33909043). Also edits incorrectly charged tRNA(Ala) via its editing domain (PubMed:27622773, PubMed:27911835, PubMed:28493438, PubMed:29273753). In presence of high levels of lactate, also acts as a protein lactyltransferase that mediates lactylation of lysine res

CytoplasmNucleus

Charcot-Marie-Tooth disease, axonal, type 2N

An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy.

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:26875626, PubMed:27616483, PubMed:28126851, PubMed:9489750). Participates in synaptic plasticity for learning and memory formation (By similarity). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus me

Cell membranePostsynaptic cell membrane

Developmental and epileptic encephalopathy 46

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:14993607, PubMed:29961870, PubMed:30140029, PubMed:31056671). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:30140029). When activated by GABA, GABAARs selec

Postsynaptic cell membraneCell membrane

Developmental and epileptic encephalopathy 79

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE79 is an autosomal dominant form characterized by onset of refractory seizures in the first months of life. Brain imaging may show hypomyelination, cerebral atrophy and thinning of the corpus callosum.

Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake (PubMed:10227690, PubMed:10954735, PubMed:18245775, PubMed:19449892, PubMed:25982116, PubMed:27078104, PubMed:32860739). Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses (PubMed:18245775, PubMed:19449892). Most important energy carrier of the brain: present at the blood-brain barrier and assures the energy-independent, facilitative trans

Cell membraneMelanosomePhotoreceptor inner segment

GLUT1 deficiency syndrome 1

A neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe intellectual disability.

Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription f

CytoplasmMembraneNucleusMitochondrion

Important modulator of glutamate signaling pathway

Cell membraneSynapse

Developmental and epileptic encephalopathy 37

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE37 is an autosomal recessive, severe form manifesting in the first years of life. Affected individuals show hyperkinetic movement disorder with choreoathetosis, spasticity, rigidity, intellectual disability, absent speech, and impaired volitional movements.

Sodium-activated K(+) channel (PubMed:37494189). Acts as an important mediator of neuronal membrane excitability (PubMed:37494189). Contributes to the delayed outward currents (By similarity). Regulates neuronal bursting in sensory neurons (By similarity). Contributes to synaptic development and plasticity (By similarity)

Cell membrane

Developmental and epileptic encephalopathy 14

A rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. This severe neurologic disorder is characterized by onset in the first 6 months of life of refractory focal seizures and arrest of psychomotor development. Ictal EEG shows discharges that arise randomly from various areas of both hemispheres and migrate from one brain region to another.

Catalyzes the hydrolysis of 1-phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) and mediates intracellular signaling downstream of G protein-coupled receptors (PubMed:9188725). Regulates the function of the endothelial barrier

Nucleus membraneCytoplasm

Developmental and epileptic encephalopathy 12

A form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG.

Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis (PubMed:12106695). As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262)

Cell membraneCell projection, dendrite

Developmental and epileptic encephalopathy 34

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE34 is characterized by onset of refractory migrating focal seizures in infancy. Affected children show developmental regression and are severely impaired globally.

May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles (PubMed:11809763). Plays a role in the brain as a key controller of neuronal and endocrine homeostatic processes (By similarity)

Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membraneCytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle

Polyendocrine-polyneuropathy syndrome

A progressive endocrine and neurodevelopmental disorder manifesting early in childhood with growth retardation and recurrent episodes of profound asymptomatic hypoglycemia. PEPNS is characterized by central hypothyroidism, hypogonadotropic hypogonadism, incomplete puberty, progressive non-autoimmune insulin-dependent diabetes mellitus, peripheral demyelinating sensorimotor polyneuropathy, and cerebellar and pyramidal signs.

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:21376300, PubMed:26875626, PubMed:26919761, PubMed:28126851, PubMed:28228639, PubMed:36959261, PubMed:7679115, PubMed:7681588, PubMed:7685113). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) (PubMed:26875626). Channel

Cell membranePostsynaptic cell membranePostsynaptic density membraneSynaptic cell membrane

Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant

An autosomal dominant neurodevelopmental disorder characterized by severe intellectual disability and developmental delay, absent speech, muscular hypotonia, dyskinesia, and hyperkinetic movements. Cortical blindness, cerebral atrophy, and seizures are present in some patients.

Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades (PubMed:29925951, PubMed:33408414). The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state (By similarity). Signaling by an activated GPCR promotes GDP release and GTP binding (By similarity). The alpha subunit has a low GTPase activity that converts bound

Cell membraneMembrane

Developmental and epileptic encephalopathy 17

A severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life and usually associated with EEG abnormalities. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements.

Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient.

Cell membrane

Generalized epilepsy with febrile seizures plus 2

A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity.

RNA-binding protein implicated in the regulation of several post-transcriptional events. Involved in pre-mRNA alternative splicing, mRNA translation and stability. Mediates exon inclusion and/or exclusion in pre-mRNA that are subject to tissue-specific and developmentally regulated alternative splicing. Specifically activates exon 5 inclusion of TNNT2 in embryonic, but not adult, skeletal muscle. Activates TNNT2 exon 5 inclusion by antagonizing the repressive effect of PTB. Acts both as an activ

NucleusCytoplasm

Developmental and epileptic encephalopathy 97

A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE97 is an autosomal dominant form.

The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel (PubMed:35293990). Plays an important role in excitation-contraction coupling (By similarity)

MembraneCell membrane

Developmental and epileptic encephalopathy 110

A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE110 is an autosomal recessive form characterized by profound global developmental delay and hypotonia apparent in infancy followed by onset of seizures in the first months or years of life.

Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acid

Endoplasmic reticulumMitochondrion

Developmental and epileptic encephalopathy 66

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE66 is an autosomal dominant form characterized by onset of seizures in first days or weeks of life.

Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex, promoting ubiquitination and proteasomal degradation of specific target proteins including TOP2A, RAB27A or itself (PubMed:27754753, PubMed:31678254). Regulates topoisomerase IIalpha/TOP2A decatenation activity and plays an important role in maintaining genomic stability (PubMed:27754753). Plays a role in lipid metabolism and inflammation through the ubiquitinated degradation of RAB27A (By simi

Chromosome, centromere, kinetochoreNucleusChromosome

Developmental and epileptic encephalopathy 100

A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE100 is an autosomal dominant, severe form characterized by global developmental delay and onset of variable types of seizures in the first months or years of life.

Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission and participates in many forms of endocytosis, such as clathrin-mediated endocytosis or synaptic vesicle endocytosis as well as rapid endocytosis (RE) (PubMed:15703209, PubMed:20428113, PubMed:29668686, PubMed:8101525, PubMed:8910402, PubMed:9362482). Associates to the membrane, through lipid binding, and self-assembles into rings and stacks of interconnected rings through oligomerization to form a helical polym

Cell membraneMembrane, clathrin-coated pitCytoplasmic vesiclePresynapseCytoplasmic vesicle, secretory vesicle, chromaffin granule

Developmental and epileptic encephalopathy 31A

An autosomal dominant epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.

Chromatin reader component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4 (PubMed:18838386, PubMed:19103755, PubMed:27103431). YEATS2 specifically recognizes and binds histone H3 crotonylated at 'Lys-27' (H3K27cr) (PubMed:27103431). Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:27103431)

Nucleus

Epilepsy, familial adult myoclonic, 4

A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME4 inheritance is autosomal dominant.

As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:29590090, PubMed:35338845). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signa

Lysosome membrane

Receptor for adenosine (By similarity). The activity of this receptor is mediated by G proteins which activate adenylyl cyclase (By similarity)

Cell membrane

E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response (PubMed:27981609, PubMed:28747347). Participates in the activation of interferon-gamma signaling by promoting proteasomal degradation of the repressor SOCS1 (PubMed:12163497). Plays a positive role in the TNFalpha and IL-1beta signaling pathways. Mechanistically, induces the 'Lys-63'-linked polyubiquitination of MAP3K7/T

CytoplasmNucleusNucleus, nuclear body

Focal segmental glomerulosclerosis and neurodevelopmental syndrome

An autosomal dominant disorder characterized by global developmental delay associated with variable features of focal segmental glomerulosclerosis, a renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and non-specific dysmorphic facial features, are commonly observed.

Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating (PubMed:36191189). Microtubule-associated protein which regulates cell division and neuronal migration during cortical development (PubMed:19734894, PubMed:28370826). Necessary for radial and tangential cell migration during brain development, possibly acting as a regulator of cell morphology and process formation during migration (PubMed:22926142)

Cytoplasm, cytoskeleton, cilium axonemeCytoplasm, cytoskeleton, flagellum axonemeCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasm, cytoskeleton, spindleCytoplasm, cytoskeleton, spindle pole

Juvenile myoclonic epilepsy 1

A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue.

Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways (PubMed:15696159, PubMed:16511572, PubMed:36732624). Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif (PubMed:15696159, PubMed:16511572, PubMed:36732624). Binding generally results in the modulation of the activity of the binding partner (PubMed:16511572). Promotes inactivation of WDR24 component of the GATOR2 complex by bindi

Cytoplasm, cytosolMitochondrion matrix

Developmental and epileptic encephalopathy 56

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE56 is an autosomal dominant condition.

As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex

Lysosome membranePeroxisome

Developmental and epileptic encephalopathy 18

A severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, early onset of refractory seizures, and thick corpus callosum and persistent cavum septum pellucidum on brain imaging.

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Contributes to the regulation of the fast action potential repolarization and in sustained high-frequency firing in neurons of the central nervous system. Homotetramer channels mediate delayed-rectifier voltage-dependent potassium currents that activate rapidly at high-threshold voltages and inactivate slowly. Forms tetrameric channels through which potassium ions pass

Cell membraneMembranePerikaryonCell projection, axonCell projection, dendritePostsynaptic cell membranePresynaptic cell membraneSynapse, synaptosomeSynapseApical cell membraneBasolateral cell membrane

Catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:8463241). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). In aerobic conditions, invol

CytoplasmCytoplasm, cytosolCytoplasmic vesicle, secretory vesicleCytoplasmic vesicle, clathrin-coated vesicle membraneLysosome

Cutis laxa, autosomal recessive, 2D

A form of cutis laxa, a disorder characterized by an excessive congenital skin wrinkling, a large fontanelle with delayed closure, a typical facial appearance with downslanting palpebral fissures, and a general connective tissue weakness. Most ARCL2D patients exhibit severe hypotonia as well as cardiovascular and neurologic involvement.

Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. AP-3 appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles. In concert w

Cytoplasmic vesicle, clathrin-coated vesicle membraneGolgi apparatus

Developmental and epileptic encephalopathy 48

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE48 is an autosomal recessive form characterized by onset of seizures in the first year of life. Affected individuals manifest global developmental delay, intellectual disability, absent speech, and poor, if any, motor development.

Endoplasmic reticulum membrane-associated E3 ubiquitin ligase that plays a critical role in mitigating endoplasmic reticulum stress, the regulation of cholesterol and lipid homeostasis, and ferroptosis (PubMed:25088257, PubMed:35941365, PubMed:39216628). Acts as a pivotal component of both the Ac/N-degron pathway (targeting the N-terminal acetyl group of substrates) and the ER-associated protein degradation-cytosol (ERAD-C) pathway (targeting misfolded substrates) (PubMed:30425097, PubMed:359413

Endoplasmic reticulum membrane

Epilepsy, familial adult myoclonic, 3

A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME3 inheritance is autosomal dominant.

May play a protective role in mucosal tissues by preventing exaggerated allergic responses

Mitochondrion

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain, but also in the pancreas and cardiovascular system. Contributes to the regulation of the action potential (AP) repolarization, duration and frequency of repetitive AP firing in neurons, muscle cells and endocrine cells and plays a role in homeostatic attenuation of electrical excitability throughout the brain (PubMed:23161216). Plays also a role in the regulation of exo

Cell membranePerikaryonCell projection, axonCell projection, dendriteMembranePostsynaptic cell membraneSynapseSynapse, synaptosomeLateral cell membraneCell membrane, sarcolemma

Developmental and epileptic encephalopathy 26

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE26 patients manifest multiple types of seizures, delayed psychomotor development, poor or absent speech, hypotonia, hypsarrhythmia.

Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:29590090, PubMed:35338845, PubMed:38006878). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1

Lysosome membrane

Epilepsy, familial adult myoclonic, 1

A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME1 inheritance is autosomal dominant.

Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes

Cytoplasm, P-body

Epilepsy, familial adult myoclonic, 6

A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME6 inheritance is autosomal dominant.

Probable histone methyltransferase, preferentially acting on 'Lys-9' of histone H3 (By similarity). Involved in the control of steroidogenesis through transcriptional repression of steroidogenesis marker genes such as CYP17A1 and LHCGR (By similarity). Forms with BHLHE22 a transcriptional repressor complex controlling genes involved in neural development and neuronal differentiation (By similarity). In the retina, it is required for rod bipolar and type 2 OFF-cone bipolar cell survival (By simil

Nucleus

Epilepsy, progressive myoclonic 10

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM10 is an autosomal recessive form characterized by progressive dysarthria, myoclonus, ataxia, cognitive decline, psychosis, dementia and spasticity, with onset in childhood. There is variability between patients.

Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR-mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term lea

Intellectual developmental disorder, autosomal dominant 5

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD5 patients show global developmental delay with delayed motor development, hypotonia, moderate-to-severe intellectual disability, and severe language impairment. Epilepsy and autism can be present in some patients.

May be involved in the proteolytic inactivation of enkephalins and neurotensin in some brain areas. May convert inactive angiotensin I into the biologically active angiotensin II (PubMed:18178555). Releases a C-terminal amino acid, with preference for large hydrophobic C-terminal amino acids and shows only very weak activity toward small amino acids and histidine (PubMed:20855895)

Secreted, extracellular space, extracellular matrix

Involved in endocytosis

Cytoplasmic vesicle, clathrin-coated vesicle membraneCell membrane

Developmental and epileptic encephalopathy 21

A severe disease characterized by intractable seizures, profound global developmental delay, and persistent severe axial hypotonia as well as appendicular hypertonia.

Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradient (PubMed:24874546, PubMed:25239001, PubMed:25725044, PubMed:26900580, PubMed:29726066, PubMed:33245860, PubMed:36696443, PubMed:36823201). Contributes to neuronal excitability by regulating action potential threshold and propagation (PubMed:24874546, PubMed:2

Cell membraneCell projection, axonCytoplasmic vesicleCell projection, podosome

Cognitive impairment with or without cerebellar ataxia

A disorder characterized by markedly delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia. Features include bilateral esophoria, strabismatic amblyopia, unsustained gaze evoked nystagmus on horizontal gaze, ataxic gait, dysmetria in the upper limbs and dysarthria, with normal strength, tone, and reflexes.

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By simi

Cell membrane

Seizures, benign familial infantile, 3

A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS3 inheritance is autosomal dominant.

As a component of the outer core of AMPAR complex, may be involved in synaptic transmission in the central nervous system. In hippocampal neurons, in presynaptic terminals, plays an important role in the final steps of neurotransmitter release, possibly by regulating Ca(2+)-sensing. In the cerebellum, may inhibit SNARE complex formation and down-regulate short-term facilitation

Cell membranePresynaptic cell membraneSynapseCell projection, axonCytoplasmic vesicle, secretory vesicle, synaptic vesicle membranePostsynaptic density membraneCell projection, dendritic spine

Episodic kinesigenic dyskinesia 1

An autosomal dominant form of paroxysmal kinesigenic dyskinesia, a neurologic condition characterized by recurrent and brief attacks of abnormal involuntary movements, triggered by sudden voluntary movement. These attacks usually have onset during childhood or early adulthood and can involve dystonic postures, chorea, or athetosis.

Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability (PubMed:16319223, PubMed:27564677, PubMed:28793216, PubMed:9872318). M-channel is composed of pore-forming subunits KCNQ2 and KCNQ3 assembled as heterotetramers (PubMed:14534157, PubMed:16319223, PubMed:27564677, PubMed:9872318). The native M-current has a slowly activating and deactivating potassium conductance which plays a critical role in determ

Cell membrane

Seizures, benign familial neonatal 2

A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset.

Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability (PubMed:24277843, PubMed:28793216, PubMed:9836639). M-channel is composed of pore-forming subunits KCNQ2 and KCNQ3 assembled as heterotetramers (PubMed:10781098, PubMed:14534157, PubMed:32884139, PubMed:37857637, PubMed:9836639). The native M-current has a slowly activating and deactivating potassium conductance which plays a critical role in determ

Cell membrane

Seizures, benign familial neonatal 1

A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. Some rare cases manifest an atypical severe phenotype associated with epileptic encephalopathy and psychomotor retardation. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset. In some patients, neonatal convulsions are followed later in life by myokymia, a benign condition characterized by spontaneous involuntary contractions of skeletal muscles fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Some patients may have isolated myokymia.

Mediates transport of gamma-aminobutyric acid (GABA) together with sodium and chloride and is responsible for the reuptake of GABA from the synapse (PubMed:30132828). The translocation of GABA, however, may also occur in the reverse direction leading to the release of GABA (By similarity). The direction and magnitude of GABA transport is a consequence of the prevailing thermodynamic conditions, determined by membrane potential and the intracellular and extracellular concentrations of Na(+), Cl(-

Cell membranePresynapse

Myoclonic-atonic epilepsy

A form of epilepsy characterized by myoclonic-atonic and absence seizures, appearing in early childhood. Patients have delayed development before the onset of seizures and show varying degrees of intellectual disability following seizure onset.

Directs RNA polymerase II nuclear import

CytoplasmNucleus

Epilepsy, progressive myoclonic 12

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM12 is an autosomal recessive form characterized by onset of tonic-clonic seizures and/or myoclonus in the second decade of life. Affected individuals develop cerebellar ataxia associated with progressive cerebral and cerebellar atrophy on brain imaging. Most patients lose ambulation and become wheelchair-bound. Additional more variable features include mild cognitive dysfunction or psychiatric manifestations, such as depression or anxiety.

This is an intracellular thiol proteinase inhibitor. Tightly binding reversible inhibitor of cathepsins L, H and B

CytoplasmNucleus

Epilepsy, progressive myoclonic 1

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM1 is an autosomal recessive form characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop.

As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway (PubMed:23723238, PubMed:25457612, PubMed:29590090, PubMed:29769719, PubMed:31548394, PubMed:35338845). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1

Lysosome membraneCytoplasm, cytosolCytoplasm, perinuclear region

Epilepsy, familial focal, with variable foci 1

An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions in different family members. Many patients have an aura and show automatisms during the seizures, whereas others may have nocturnal seizures. There is often secondary generalization. Some patients show abnormal interictal EEG, and some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. Penetrance of the disorder is incomplete.

Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:14993607, PubMed:18514161, PubMed:22243422, PubMed:22303015, PubMed:24909990, PubMed:26950270, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMe

Postsynaptic cell membraneCell membraneCytoplasmic vesicle membrane

Epilepsy, childhood absence 5

A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood.

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA

Cell membrane

Spinocerebellar ataxia 6

Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA6 is an autosomal dominant cerebellar ataxia (ADCA), mainly caused by expansion of a CAG repeat in the coding region of CACNA1A. There seems to be a correlation between the repeat number and earlier onset of the disorder.

Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle (PubMed:11566871, PubMed:19641205, PubMed:24515575, PubMed:38945283). Also mediates the uptake of L-cysteinesulfinate (3-sulfino-L-alanine) by mitochondria in exchange of L-glutamate and proton (PubMed:11566871). Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton trans

Mitochondrion inner membrane

Developmental and epileptic encephalopathy 39 with leukodystrophy

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:24272827, PubMed:24863970, PubMed:26875626, PubMed:26919761, PubMed:27839871, PubMed:28095420, PubMed:28126851, PubMed:38538865, PubMed:8768735). Participates in synaptic plasticity for learning and memory formation by contributing to the long-term depression (LTD) of hippocampus membrane currents

Cell membranePostsynaptic cell membraneCell projection, dendriteLate endosomeLysosomeCytoplasm, cytoskeleton

Intellectual developmental disorder, autosomal dominant 6, with or without seizures

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD6 additional features may include seizures, hypotonia, abnormal movements, such as dystonia, and autistic features.

High-affinity sodium/citrate cotransporter that mediates the entry of citrate into cells, which is a critical participant of biochemical pathways (PubMed:12445824, PubMed:12826022, PubMed:26324167, PubMed:26384929, PubMed:30054523, PubMed:33597751, PubMed:39622972). May function in various metabolic processes in which citrate has a critical role such as energy production (Krebs cycle), fatty acid synthesis, cholesterol synthesis, glycolysis, and gluconeogenesis (PubMed:12826022). Transports citr

Cell membrane

Developmental and epileptic encephalopathy 25, with amelogenesis imperfecta

An autosomal recessive disease characterized by subclinical seizures appearing in the first days of life, evolving to severe epileptic disease. Affected individuals have profound or severe delayed development with lack of speech, and most patients do not acquire the ability to sit. Additional variable features include axial hypotonia, peripheral hypertonia, and abnormal involuntary movements such as dystonia and choreoathetosis. Dental abnormalities, including delayed eruption, hypodontia, tooth hypoplasia, yellow discoloration, thin enamel, and enamel chipping are observed in most patients.

Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions (PubMed:15351778, PubMed:28086084). Displays lower selectivity for K(+) over Na(+) ions (PubMed:28086084). Contributes to the native pacemaker currents in heart (If) and in the generation of the I(h) current which controls neuron excitability (PubMed:29936235, PubMed:30351409). Participates in cerebellar mechanisms of motor learning (By similarity). May mediate responses to sour stimuli (By similarity)

Cell membrane

Developmental and epileptic encephalopathy 24

A disease characterized by early-onset seizures, intellectual disability of varying degrees, and behavioral disturbances or autistic features in most individuals.

Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+) (PubMed:14523450, PubMed:29330545, PubMed:31152168). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of sys

Cell membrane

Paroxysmal non-kinesigenic dyskinesia 3 with or without generalized epilepsy

An autosomal dominant neurologic disorder characterized by absence seizures, generalized tonic-clonic seizures, paroxysmal nonkinesigenic dyskinesia and involuntary dystonic or choreiform movements. Onset is usually in childhood. Patients may have seizures only, dyskinesia only, or both.

Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance. May function through the PLXNA4 receptor expressed by mossy cell axons (Microbial infection) Acts as a receptor for P.sordellii toxin TcsL in the in the vascular endothelium

Cell membrane

Epilepsy, progressive myoclonic 11

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM11 is an autosomal dominant form. Clinical features include normal or mildly delayed early development, developmental regression after seizures onset, inability to walk, severely impaired intellectual development, poor or absent speech, spasticity, ataxia, and intention tremor. Brain imaging shows cerebellar atrophy in some patients.

Voltage-gated potassium channel that opens in response to the voltage difference across the membrane and through which potassium ions pass in accordance with their electrochemical gradient (PubMed:25401298, PubMed:35840580). The mechanism is time-dependent and inactivation is slow (By similarity). Plays an important role in the rapid repolarization of fast-firing brain neurons (By similarity). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proport

Cell membraneCell projection, axonPresynaptic cell membrane

Epilepsy, progressive myoclonic 7

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM7 is an autosomal dominant form characterized by myoclonic epilepsy apparent in the first or second decades of life. Cognitive function may decline in some patients.

Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensiti

Synaptic cell membraneCell membrane

Epilepsy, nocturnal frontal lobe, 4

An autosomal dominant focal epilepsy characterized by nocturnal seizures associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking.

Chromosomal protein that binds to methylated DNA. It can bind specifically to a single methyl-CpG pair. It is not influenced by sequences flanking the methyl-CpGs. Mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A. Binds both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC)-containing DNA, with a preference for 5-methylcytosine (5mC)

Nucleus

Angelman syndrome

A neurodevelopmental disorder characterized by severe motor and intellectual retardation, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, open-mouthed expression revealing the tongue.

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the cardiovascular system. Prevents aberrant action potential firing and regulates neuronal output. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage differen

Cell membraneMembraneCell projection, axonSynapseEndoplasmic reticulum membraneCell projection, lamellipodium membraneSynapse, synaptosomePresynaptic cell membraneCell projection, dendriteCell junction, paranodal septate junction

Developmental and epileptic encephalopathy 32

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE32 inheritance is autosomal dominant.

Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting (Microbial infection) Acts as a receptor for enterovirus 71

Lysosome membrane

Epilepsy, progressive myoclonic 4, with or without renal failure

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM4 is an autosomal recessive form associated with renal failure in some cases. Cognitive function is preserved.

Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane

Cytoplasm, cytoskeletonCytoplasm, cell cortex

Developmental and epileptic encephalopathy 5

A disorder characterized by seizures associated with hypsarrhythmia, profound intellectual disability with lack of visual attention and speech development, as well as spastic quadriplegia.

Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:10449790, PubMed:16412217, PubMed:26950270). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain one or two GABA active binding sites located at the alpha and beta subunit interfaces, depending on subunit composition (By similarity). When activated b

Postsynaptic cell membraneCell membrane

Developmental and epileptic encephalopathy 45

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.

Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis. Base pairing between the mRNA codon and the aa-tRNA anticodon promotes GTP hydrolysis, releasing the aa-tRNA from EEF1A1 and allowing its accommodation into the ribosome (By similarity). The growing protein chain is subsequently transferred from the P-site peptidyl tRNA to the A-site aa-tRNA, extending it by one amino acid

Endoplasmic reticulum membrane

Developmental and epileptic encephalopathy 33

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.

Transcription factor (PubMed:22194193, PubMed:31691806). Binds to specific sequence motif 5'-TAATTA-3' in regulatory elements of target genes, such as histone demethylase KDM5C (PubMed:22194193, PubMed:31691806). Positively modulates transcription of KDM5C (PubMed:31691806). Activates expression of KDM5C synergistically with histone lysine demethylase PHF8 and perhaps in competition with transcription regulator ZNF711; synergy may be related to enrichment of histone H3K4me3 in regulatory element

Nucleus

Lissencephaly, X-linked 2

A classic type lissencephaly associated with abnormal genitalia. Patients have severe congenital or postnatal microcephaly, lissencephaly, agenesis of the corpus callosum, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and ambiguous or underdeveloped genitalia.

May act as a GTPase-activating protein for Rab family protein(s) (PubMed:20727515, PubMed:20797691). Involved in neuronal projections development, probably through a negative modulation of ARF6 function (PubMed:20727515). Involved in the regulation of synaptic vesicle trafficking (PubMed:31257402)

Cell membraneCytoplasmCytoplasmic vesicle membranePresynapse

Familial infantile myoclonic epilepsy

A subtype of idiopathic epilepsy starting in early infancy and manifesting as myoclonic seizures, febrile convulsions, and tonic-clonic seizures.

May be involved in the control of excitability of cortical neurons

Cell membraneCytoplasm, cytosol

Epilepsy, progressive myoclonic 3, with or without intracellular inclusions

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM3 is an autosomal recessive, severe, form with early onset. Multifocal myoclonic seizures begin between 16 and 24 months of age after normal initial development. Neurodegeneration and regression occur with seizure onset. Other features include intellectual disability, dysarthria, truncal ataxia, and loss of fine finger movements. EEG shows slow dysrhythmia, multifocal and occasionally generalized epileptiform discharges. In some patients, ultrastructural findings on skin biopsies identify intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis.

Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure. Convergent extension is a complex morphogenetic process during which cells elongate, move mediolaterally, and intercalate between neighboring cells, leading to convergence toward the mediolateral axis and extension along the anteroposterior axis. Necessary for nuclear localization of REST. May serve as nuclear receptor

Nucleus membraneCytoplasm, cytosol

Epilepsy, progressive myoclonic 1B

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM1B is an autosomal recessive form characterized by myoclonus that progressed in severity over time, tonic-clonic seizures and ataxia.

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:20890276, PubMed:23933818, PubMed:23933819, PubMed:23933820, PubMed:24504326, PubMed:26875626, PubMed:26919761, PubMed:28242877, PubMed:36117210, PubMed:38538865, PubMed:8768735). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the slow phase of excita

Cell projection, dendritic spineCell membraneSynapsePostsynaptic cell membraneCytoplasmic vesicle membrane

Epilepsy, focal, with speech disorder and with or without impaired intellectual development

An autosomal dominant, highly variable neurologic disorder. Features range from severe early-onset seizures associated with delayed psychomotor development, persistent speech difficulties, and intellectual disability to a more benign entity characterized by childhood onset of mild or asymptomatic seizures associated with transient speech difficulties followed by remission of seizures in adolescence and normal psychomotor development. The disorder encompasses several clinical entities, including Landau-Kleffner syndrome, epileptic encephalopathy with continuous spike and wave during slow-wave sleep, autosomal dominant rolandic epilepsy, intellectual disability and speech dyspraxia, and benign epilepsy with centrotemporal spikes.

Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:14993607, PubMed:16412217, PubMed:23909897, PubMed:2538761, PubMed:25489750, PubMed:27864268, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit in

Postsynaptic cell membraneCell membraneCell projection, dendriteCytoplasmic vesicle membrane

Developmental and epileptic encephalopathy 74

A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE74 is an autosomal dominant form with onset in the first year of life.

Involved in transport of proteins from the cis/medial-Golgi to the trans-Golgi network

Golgi apparatus, cis-Golgi network membraneGolgi apparatus membraneEndoplasmic reticulum membrane

Epilepsy, progressive myoclonic 6

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. EPM6 is an autosomal recessive form characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade.

Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient.

Cell membraneBasal cell membrane

Epilepsy, familial focal, with variable foci 4

An autosomal dominant form of epilepsy characterized by focal seizures arising from different cortical regions, including the temporal, frontal, parietal, and occipital lobes. Seizure types commonly include temporal lobe epilepsy, frontal lobe epilepsy, and nocturnal frontal lobe epilepsy. Some patients may have intellectual disability or autism spectrum disorders. Seizure onset usually occurs in the first or second decades, although later onset has been reported, and there is phenotypic variability within families. A subset of patients have structural brain abnormalities. Penetrance of the disorder is incomplete. FFEVF4 is characterized by onset of focal seizures in the first years of life.

Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin (PubMed:11880376, PubMed:19265707, PubMed:19285087, PubMed:26329378, PubMed:9442076). May be involved in the formation or reorganization of synaptic connections as well as for synaptic plasticity in the adult nervous system. May protect neurons from cell damage by tissue-type plasminogen activator (Probable)

SecretedCytoplasmic vesicle, secretory vesicle lumenPerikaryon

Encephalopathy, familial, with neuroserpin inclusion bodies

A neurodegenerative disease clinically characterized by dementia. Additional features include intellectual decline, psychic seizures, progressive myoclonic epilepsy, and cerebral atrophy. Histologically, it is characterized by the presence of eosinophilic inclusion bodies (called Collins bodies) throughout the deeper layers of the cerebral cortex, leading to neuronal death.

E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for pro

Endoplasmic reticulumNucleus

Myoclonic epilepsy of Lafora 2

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. MELF2 is an autosomal recessive, severe form characterized by onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, myoclonic jerks, generalized seizures, and often visual hallucination. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. At the cellular level, MELF2 is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle.