Mitochondrial glutamate/H(+) symporter. Responsible for the transport of glutamate from the cytosol into the mitochondrial matrix with the concomitant import of a proton (PubMed:11897791). Plays a role in the control of glucose-stimulated insulin secretion (By similarity)

Mitochondrion inner membrane

Developmental and epileptic encephalopathy 3

A severe 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. DEE3 is characterized by a very early onset, erratic and fragmentary myoclonus, massive myoclonus, partial motor seizures and late tonic spasms. The prognosis is poor, with no effective treatment, and children with the condition either die within 1 to 2 years after birth or survive in a persistent vegetative state.

Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of 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. The influx of Na+ ions provoke

Cell membranePerikaryonCell projectionCell projection, axonSecreted

Generalized epilepsy with febrile seizures plus 1

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.

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.

Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis

Membrane

Developmental and epileptic encephalopathy 55

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. DEE55 is an autosomal recessive condition.

Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk

Secreted

Regulator of cell proliferation and apoptosis (PubMed:21801820). It likely functions as a substrate-adapter that recruits key substrates, e.g. MSI2, to CUL3-based ubiquitin ligase complexes for degradation (PubMed:15107402, PubMed:27941885). Required for MSI2 ubiquitination and degradation (PubMed:27941885)

Developmental and epileptic encephalopathy 64

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. DEE64 is an autosomal dominant form characterized by onset of seizures usually in the first year of life. Seizure types are variable and include focal dyscognitive and generalized tonic-clonic seizures, as well as febrile seizures in the mildest affected individuals. Seizures tend to respond to medical treatment.

Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells (PubMed:30343943). They 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-1E gives rise to R-type calcium currents. R-type calcium channels belong to the 'high-voltage activated' (HVA) group and are blocked by nickel. They are however insensit

Membrane

Developmental and epileptic encephalopathy 69

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. DEE69 is an autosomal dominant form characterized by refractory seizures, hypotonia, and profoundly impaired development often associated with macrocephaly, hyperkinetic movements, and contractures. The disorder can sometimes result in early death. Some patients may have a favorable seizure response to topiramate medication.

Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways (PubMed:10446192, PubMed:10446193, PubMed:15385968, PubMed:20852255, PubMed:28453785). Through its two catalytic activities, PNK ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone (PubMed:10446192, PubMed:10446

NucleusChromosome

Microcephaly, seizures, and developmental delay

An autosomal recessive neurodevelopmental disorder characterized by infantile-onset seizures, microcephaly, severe intellectual disability and delayed motor milestones with absent speech or only achieving a few words. Most patients also have behavioral problems with hyperactivity. Microcephaly is progressive and without neuronal migration or structural abnormalities, consistent with primary microcephaly.

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 kidney (PubMed:19903818, PubMed:8845167). Contributes to the regulation of the membrane potential and nerve signaling, and prevents neuronal hyperexcitability (PubMed:17156368). Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alte

Cell membraneMembraneCell projection, axonCytoplasmic vesiclePerikaryonEndoplasmic reticulumCell projection, dendriteCell junctionSynapsePresynaptic cell membranePresynapse

Episodic ataxia 1

An autosomal dominant disorder characterized by brief episodes of ataxia and dysarthria. Neurological examination during and between the attacks demonstrates spontaneous, repetitive discharges in the distal musculature (myokymia) that arise from peripheral nerve. Nystagmus is absent.

Transcriptional regulator implicated in neuronal determination. Mediates calcium-dependent transcription activation by binding to E box-containing promoter. Critical factor essential for the repression of the genetic program for neuronal differentiation; prevents the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. Induces transcription of ZEB1, which in turn represses neuronal differentiation by down-regulating REST expression. Plays a

Nucleus

Developmental and epileptic encephalopathy 72

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. DEE72 is an autosomal dominant form with variable severity and onset in infancy.

Antiporter that exchanges vesicular protons for cytosolic 4-aminobutanoate or to a lesser extend glycine, thus allowing their secretion from nerve terminals. The transport is equally dependent on the chemical and electrical components of the proton gradient (By similarity). May also transport beta-alanine (By similarity). Acidification of GABAergic synaptic vesicles is a prerequisite for 4-aminobutanoate uptake (By similarity)

Cytoplasmic vesicle membranePresynapse

Generalized epilepsy with febrile seizures plus 12

An autosomal dominant neurologic disorder with variable expressivity and incomplete penetrance. Affected individuals have variable types of seizures, most often febrile seizures, sometimes combined with non-febrile focal or generalized seizures. Rarely, afebrile tonic-clonic seizures have been observed.

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.

G-protein coupled receptor activated by glutamate that regulates axon outgrowth through the MAPK-cAMP-PKA signaling pathway during neuronal development (PubMed:33500274). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase that it inhibits (PubMed:9473604)

Cell membrane

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities

An autosomal recessive neurodevelopmental disorder characterized by global developmental delay, hypotonia, severe to profound intellectual disability, early-onset epilepsy, and microcephaly. Neuroimaging shows cerebral atrophy, thin corpus callosum and hypomyelination in a majority of cases. Death in childhood may occur.

Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis

Membrane

Multiple congenital anomalies-hypotonia-seizures syndrome 4

An autosomal recessive syndrome characterized by onset of refractory seizures in the first months of life. Additional clinical features include severe global developmental delay, dysmorphic facial features, and skeletal, renal and ophthalmic anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI).

Mediates phosphorylation of MECP2 (PubMed:15917271, PubMed:16935860). May regulate ciliogenesis (PubMed:29420175)

NucleusCytoplasm, cytoskeleton, cilium basal bodyCytoplasm, cytoskeleton, microtubule organizing center, centrosome

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.

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.

Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:14506254, PubMed:15265858, PubMed:26690923, PubMed:7521911). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative

Cell membrane

Developmental and epileptic encephalopathy 41

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. DEE41 inheritance is autosomal dominant.

Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. Phosphorylates HDAC4, HDAC5, PPME1, SREBF1, CRTC1/TORC1. Inhibits CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signaling (PubMed:29211348). Acts as a tumor suppressor and plays a key role in p53/TP53

CytoplasmNucleus

Developmental and epileptic encephalopathy 30

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.