Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA

Cytoplasm, cytosol

Hypomyelination with brainstem and spinal cord involvement and leg spasticity

An autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild intellectual disability. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord.

Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone

Mitochondrion inner membrane

Mitochondrial complex I deficiency, nuclear type 13

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN13 transmission pattern is consistent with autosomal recessive inheritance.

Transcription factor with repressor activity involved in the regulation of axon-glial interactions at myelin paranodes in oligodendrocytes. Binds to the consensus DNA sequence 5'-(A/T)TTAATGA-3'. In oligodendrocytes, binds to MBP and PLP1 promoter regions

Nucleus

Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy

An autosomal recessive neurodegenerative disorder characterized by early-onset hypotonia which progresses to a pyramidal syndrome with ataxia, spasticity, hyperreflexia, weakness and loss of ambulation. Brain imaging shows cerebellar atrophy and hypomyelinating leukodystrophy.

Major component of the axial/lateral elements of synaptonemal complexes (SCS) during meiotic prophase. Plays a role in the assembly of synaptonemal complexes. Required for normal meiotic chromosome synapsis during oocyte and spermatocyte development and for normal male and female fertility. Required for insertion of SYCP3 into synaptonemal complexes. May be involved in the organization of chromatin by temporarily binding to DNA scaffold attachment regions. Requires SYCP3, but not SYCP1, in order

NucleusChromosome

Spermatogenic failure 1

An infertility disorder characterized by azoospermia due to spermatogenic arrest during meiosis. Meiotic arrest is characterized by germ cells that enter meiosis and undergo the first chromosomal reduction from 4n to 2n, but that are then unable to proceed further. This results in tubules containing spermatocytes as the latest developmental stage of germ cells. Meiotically arrested spermatocytes accumulate in the tubules and degenerate. Both autosomal recessive and autosomal dominant inheritance have been reported.

Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids. Active on a variety of saturated and unsaturated aliphatic aldehydes between 6 and 24 carbons in length (PubMed:18035827, PubMed:18182499, PubMed:22633490, PubMed:25047030, PubMed:9133646, PubMed:9662422). Responsible for conversion of the sphingosine 1-phosphate (S1P) degradation product hexadecenal to hexadecenoic acid (PubMed:22633490)

Microsome membraneEndoplasmic reticulum membrane

Sjoegren-Larsson syndrome

An autosomal recessive neurocutaneous disorder characterized by a combination of severe intellectual disability, spastic di- or tetraplegia and congenital ichthyosis. Ichthyosis is usually evident at birth with varying degrees of erythema and scaling, neurologic symptoms appear in the first or second year of life. Most patients have an IQ of less than 60. Additional clinical features include glistening white spots on the retina, seizures, short stature and speech defects.

Mitochondrial NAD(+) kinase that phosphorylates NAD(+) to yield NADP(+). Can use both ATP or inorganic polyphosphate as the phosphoryl donor. Also has weak NADH kinase activity in vitro; however NADH kinase activity is much weaker than the NAD(+) kinase activity and may not be relevant in vivo

Mitochondrion

2,4-dienoyl-CoA reductase deficiency

A rare, autosomal recessive, inborn error of polyunsaturated fatty acids and lysine metabolism, resulting in mitochondrial dysfunction. Affected individuals have a severe encephalopathy with neurologic and metabolic abnormalities beginning in early infancy. Laboratory studies show increased C10:2 carnitine levels and hyperlysinemia.

Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit (PubMed:25858979, PubMed:27023709, PubMed:31048492). Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed (Pub

Cytoplasm, cytosol

Leukoencephalopathy with vanishing white matter 4

An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers (PubMed:22328087). Regulates the response of astrocytes to hypo-osmosis by promoting calcium influx (PubMed:22328087). May function as regulatory protein of membrane protein complexes such as ion channels (Probable)

MembraneCell membraneCytoplasm, perinuclear regionEndoplasmic reticulum

Megalencephalic leukoencephalopathy with subcortical cysts 1

A syndrome of cerebral leukoencephalopathy and megalencephaly characterized by ataxia, spasticity, seizures, delay in motor development and mild intellectual disability. The brain appears swollen on magnetic resonance imaging, with diffuse white-matter abnormalities and the invariable presence of subcortical cysts in frontal and temporal lobes.

Involved in peroxisomal proliferation (PubMed:9792670). May regulate peroxisome division by recruiting the dynamin-related GTPase DNM1L to the peroxisomal membrane (PubMed:12618434). Promotes membrane protrusion and elongation on the peroxisomal surface (PubMed:20826455)

Peroxisome membrane

Peroxisome biogenesis disorder 14B

An autosomal recessive peroxisome biogenesis disorder characterized clinically by mild intellectual disability, congenital cataracts, progressive hearing loss, and polyneuropathy. Additionally, recurrent migraine-like episodes following mental stress or physical exertion, not a common feature in peroxisome disorders, are observed.

Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53

CytoplasmPeroxisome membrane

Peroxisome biogenesis disorder complementation group 14

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids

CytoplasmNucleus

Canavan disease

A rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demyelination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.

May be involved in vesicular trafficking from the Golgi apparatus to the cell membrane. Plays a role in the maintenance of the myelin sheath, and in axon-glia and glia-glia interactions

MembraneCell membrane

Leukodystrophy, hypomyelinating, 28

A form of hypomyelinating leukodystrophy, a group of heterogeneous disorders characterized by persistent deficit of myelin observed on brain imaging. HLD28 is an autosomal recessive form characterized by developmental delay and nystagmus in infancy, followed by significant learning disabilities and progressive motor deterioration within the first decade.

Component of the U7 snRNP complex that is involved in the histone 3'-end pre-mRNA processing (PubMed:11574479, PubMed:16914750, PubMed:33230297). Increases U7 snRNA levels but not histone 3'-end pre-mRNA processing activity, when overexpressed (PubMed:11574479, PubMed:16914750). Required for cell cycle progression from G1 to S phases (By similarity). Binds specifically to the Sm-binding site of U7 snRNA (PubMed:11574479, PubMed:16914750)

Nucleus

Aicardi-Goutieres syndrome 8

A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. AGS8 inheritance is autosomal recessive.

Major cellular 3'-to-5' DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3' termini (PubMed:10391904, PubMed:10393201, PubMed:17293595). Prevents cell-intrinsic initiation of autoimmunity (PubMed:10391904, PubMed:10393201, PubMed:17293595). Acts by metabolizing DNA fragments from endogenous retroelements, including L1, LTR and SINE elements (PubMed:10391904, PubMed:10393201, PubMed:17293595). Plays a key role in degradation of DNA fragment

NucleusCytoplasm, cytosolEndoplasmic reticulum membrane

Aicardi-Goutieres syndrome 1

A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.

Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging-strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes

Nucleus

Aicardi-Goutieres syndrome 3

A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.

GFAP, a class-III intermediate filament, is a cell-specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells

Cytoplasm

Alexander disease

A rare disorder of the central nervous system. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death within the first decade. Infants with Alexander disease develop a leukodystrophy with macrocephaly, seizures, and psychomotor retardation. Patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic inclusions in astrocytes.

Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit (PubMed:25858979, PubMed:27023709, PubMed:31048492). Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed (Pub

Cytoplasm, cytosol

Leukoencephalopathy with vanishing white matter 5

An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Non-catalytic component of the multisynthase complex. Stimulates the catalytic activity of cytoplasmic arginyl-tRNA synthase (PubMed:10358004). Binds tRNA. Possesses inflammatory cytokine activity (PubMed:11306575). Negatively regulates TGF-beta signaling through stabilization of SMURF2 by binding to SMURF2 and inhibiting its SMAD7-mediated degradation (By similarity). Involved in glucose homeostasis through induction of glucagon secretion at low glucose levels (By similarity). Promotes dermal f

NucleusCytoplasm, cytosolSecretedEndoplasmic reticulumGolgi apparatus

Leukodystrophy, hypomyelinating, 3

A severe autosomal recessive hypomyelinating leukodystrophy characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system.

ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:17382883). Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1/WRB and CAMLG/GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dime

CytoplasmEndoplasmic reticulumNucleus, nucleolus

Cardiomyopathy, dilated, 2H

A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2H is an autosomal recessive form characterized by rapid progression and death in early infancy.

Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:26571211). HYCC1 plays a key role in oligodendrocytes formation, a cell type with expanded plasma membrane that requires generation of PtdIns(4)P (PubMed:26571211). Its role in oligodendrocytes formation probably explains its importance in myelination of the central and periphe

Cytoplasm, cytosolCell membrane

Leukodystrophy, hypomyelinating, 5

A hypomyelinating leukodystrophy associated with congenital cataract. It is clinically characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. Affected individuals experience progressive pyramidal and cerebellar dysfunction, muscle weakness and wasting prevailingly in the lower limbs. Mental deficiency ranges from mild to moderate. HLD5 shows clinical variability, but features of hypomyelination combined with increased periventricular white matter water content are consistently observed.

Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates. Transcribes 47S pre-rRNAs from multicopy rRNA gene clusters, giving rise to 5.8S, 18S and 28S ribosomal RNAs (PubMed:11250903, PubMed:11283244, PubMed:16858408, PubMed:34671025, PubMed:34887565, PubMed:36271492). Pol I-mediated transcription cycle proceeds through transcription initiation, transcription elongati

Nucleus, nucleolusChromosome

Acrofacial dysostosis, Cincinnati type

A form of acrofacial dysostosis, a group of disorders characterized by malformations of the craniofacial skeleton and, in some patients, the limbs. AFDCIN patients may also have structural cardiac defects and neurologic abnormalities including developmental delay, hypotonia, motor delay and seizures. AFDCIN inheritance is autosomal dominant.

Mechanosensitive cation channel with low conductance and high activation threshold (PubMed:30382938, PubMed:31587869, PubMed:37543036). In contrast to TMEM63B, does not show phospholipid scramblase activity (PubMed:39716028). Acts as a regulator of lysosomal morphology by mediating lysosomal mechanosensitivity (By similarity). Important for the baby's first breath and respiration throughout life (PubMed:38127458). Upon lung inflation conducts cation currents in alveolar type 1 and 2 cells trigge

Lysosome membraneEarly endosome membraneCell membrane

Leukodystrophy, hypomyelinating, 19, transient infantile

An autosomal dominant disorder characterized by marked hypomyelination on brain imaging, congenital nystagmus, and motor delay manifesting in early infancy. Both neurologic impairment and abnormal brain imaging spontaneously resolve during childhood.

Has sphingolipid-delta-4-desaturase activity. Converts D-erythro-sphinganine to D-erythro-sphingosine (E-sphing-4-enine) (PubMed:11937514, PubMed:30620337, PubMed:30620338). Catalyzes the equilibrium isomerization of retinols (By similarity)

Mitochondrion membraneEndoplasmic reticulum membrane

Leukodystrophy, hypomyelinating, 18

An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with progressive atrophy of the corpus callosum, thalami and cerebellum, and peripheral neuropathy. Clinical features include very poor psychomotor development, dystonia, severe spasticity, seizures, and failure to thrive.

Required for assembly and stability of the aminoacyl-tRNA synthase complex (PubMed:19131329). Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor

Cytoplasm, cytosolNucleus

Leukodystrophy, hypomyelinating, 17

An autosomal recessive neurodevelopmental disorder characterized by atrophy of cerebral cortex, spinal cord and cerebellum, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination observed on brain imaging. Clinical manifestations include lack of development, absent speech, microcephaly, spasticity, seizures, and contractures.

Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex. Within the complex it catalyzes the attachment of both L-glutamate and L-proline to their cognate tRNAs in a two-step reaction where the amino acid is first activated by ATP to form a covalent intermediate with AMP. Subsequently, the activated amino acid is transferred to the acceptor end of the cognate tRNA to form L-glutamyl-tRNA(Glu) and L-prolyl-t

Cytoplasm, cytosolMembrane

Leukodystrophy, hypomyelinating, 15

An autosomal recessive disorder characterized by hypomyelinating leukodystrophy with thinning of the corpus callosum. Clinical features include motor and cognitive impairment appearing in the first or second decade of life, dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss.

Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (PubMed:10604985, PubMed:9490415, PubMed:9655483). TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation (PubMed:9490415). Also has an inhibitory role in

Cell membrane

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

A recessively inherited disease characterized by presenile dementia along with large-scale destruction of cancellous bones. Initial symptoms, starting in the twenties, are pain and swelling resulting from cysts in the wrists and ankles. Extremity bone fractures could occur with minor trauma. At around 30 years of age, patients gradually develop neuropsychiatric symptoms, including epileptic seizures, agnosia, apraxia, speech disorder, memory disturbance, euphoria, and loss of social inhibitions. The disorder usually leads to death in the fifth decade of life.

Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118). PEX26 is therefore required for the formation of the PEX1-PEX6 AAA ATPase complex, a complex that mediates the extraction of the PEX5 receptor from peroxisomal membrane (PubMed:12717447, PubMed:12851857, PubMed:16257970, PubMed:16763195, PubMed:16854980, PubMed:21362118)

Peroxisome membrane

Peroxisome biogenesis disorder complementation group 8

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:28765278, PubMed:8858165, PubMed:9653144). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion o

Peroxisome membrane

Peroxisome biogenesis disorder complementation group 13

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

This is the major myelin protein from the central nervous system. It plays an important role in the formation or maintenance of the multilamellar structure of myelin

Cell membraneMyelin membrane

Leukodystrophy, hypomyelinating, 1

An X-linked recessive disorder of the central nervous system in which myelin is not formed properly. Clinically characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay.

Chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp10, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix (PubMed:11422376, PubMed:1346131). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In

Mitochondrion matrix

Spastic paraplegia 13, autosomal dominant

A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body.

In neurons, involved in the transport of late endosomes/lysosomes (PubMed:25066864). May be involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking (PubMed:25066864). May act as a molecular brake for retrograde transport of late endosomes/lysosomes, possibly via its interaction with MAP6 (By similarity). In motoneurons, may mediate the axonal transport of lysosomes and axonal sorting at the initial segment (By similarity). It remains unclear whether TMEM106B affect

Late endosome membraneLysosome membraneCell membrane

Frontotemporal dementia 2

A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. Gestural apraxia, parkinsonism, visual loss, and visual hallucinations are present in 25 to 40% of patients.

Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5-carboxylate to L-proline using NAD(P)H (PubMed:23024808, PubMed:2722838, PubMed:6894153). At physiologic concentrations, has higher specific activity in the presence of NADH (PubMed:23024808, PubMed:2722838, PubMed:6894153). Involved in cellular response to oxidative stress (PubMed:25865492). In some cell types, such as erythrocytes, its primary function may be the generation of

CytoplasmMitochondrion

Leukodystrophy, hypomyelinating, 10

An autosomal recessive neurologic disorder characterized by postnatal microcephaly, severely delayed psychomotor development, hypomyelination, and reduced cerebral white-matter volume.

Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia (PubMed:27477018, PubMed:29518356). Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, a

Cell membraneSecreted

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

An autosomal recessive disease characterized by presenile frontal dementia with leukoencephalopathy and basal ganglia calcification. In most cases the disorder first manifests in early adulthood as pain and swelling in ankles and feet, followed by bone fractures. Neurologic symptoms manifest in the fourth decade of life as a frontal lobe syndrome with loss of judgment, euphoria, and disinhibition. Progressive decline in other cognitive domains begins to develop at about the same time. The disorder culminates in a profound dementia and death by age 50 years.

Voltage-gated and osmosensitive chloride channel. Forms a homodimeric channel where each subunit has its own ion conduction pathway. Conducts double-barreled currents controlled by two types of gates, two fast glutamate gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Displays inward rectification currents activated upon membrane hyperpolarization and extracellular hypotonicity (PubMed:16155254, PubMed:17567819, PubMed:19

Cell membraneBasolateral cell membraneCell projection, dendritic spine membraneCell projection, axon

Epilepsy, idiopathic generalized 11

A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain.

Forms part of a macromolecular complex that catalyzes the attachment of specific amino acids to cognate tRNAs during protein synthesis (PubMed:25288775). Modulates the secretion of AIMP1 and may be involved in generation of the inflammatory cytokine EMAP2 from AIMP1 (PubMed:17443684)

CytoplasmCytoplasm, cytosol

Leukodystrophy, hypomyelinating, 9

An autosomal recessive neurodegenerative disorder characterized by delayed psychomotor development, severe spasticity, nystagmus, and ataxia associated with diffuse hypomyelination apparent on brain MRI.

Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. Synthesizes 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci (PubMed:19609254, PubMed:19631370, PubMed:20413673, PubMed:33335104, PubMed:33558764, PubMed:33558766, PubMed:34675218, PubMed:35637192, PubMed:9331371). Pol III-mediated transcription cycle proceeds through transcription init

NucleusCytoplasm, cytosol

Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism

An autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability.

Zinc ion transporter that mediates zinc efflux and plays a crucial role in intracellular zinc homeostasis (PubMed:25130899, PubMed:31697912, PubMed:36204728). Binds the divalent cations Zn(2+), Ni(2+), and to a minor extent Cu(2+) (By similarity). Is a functional modulator of P2X purinoceptors, including P2RX1, P2RX3, P2RX4 and P2RX7 (PubMed:32492420). Plays a role in central nervous system development and is required for myelination, and survival and proliferation of oligodendrocytes (PubMed:35

Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membraneEarly endosome membraneLate endosome membraneLysosome membraneCell membrane

Leukodystrophy, hypomyelinating, 25

A form of hypomyelinating leukodystrophy, a group of heterogeneous disorders characterized by persistent deficit of myelin observed on brain imaging. HLD25 is an autosomal dominant form with onset in early infancy and characterized by nystagmus, hypotonia, and delayed global development. Most patients show gradual clinical improvement over time with resolution of the nystagmus in early childhood. Many achieve developmental milestones and may have normal cognition, although some affected individuals may have persistent neurologic deficits. Brain imaging shows hypomyelination that may also improve with time.

E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of SIN3B (By similarity). Independently of its E3 ligase activity, acts as a CTNNB1 stabilizer through USP7-mediated deubiquitination of CTNNB1 promoting Wnt signaling (PubMed:25266658, PubMed:33964137). Plays a critical role in the regulation of nuclear lamina (PubMed:33964137)

CytoplasmNucleus

Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy

An autosomal recessive neurodegenerative disorder with systemic manifestations. Affected individuals show delayed motor development and ataxic gait in early childhood that progresses to spastic paraplegia with loss of ambulation in the first decades of life. Additional features include progressive sensorineural hearing loss, hepatic dysfunction, and dilated cardiomyopathy. Death occurs in the first or second decades. Brain imaging shows hypomyelination, diffuse white matter abnormalities, and thin corpus callosum.

Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer (PubMed:15071506, PubMed:20018847, PubMed:27653677, PubMed:29868776, PubMed:30626644, PubMed:38377992, PubMed:38383785). The so-called ufmylation, requires the UFM1-activating E1 enzyme UBA5, the UFM1-conjugating E2 enzyme UFC1, and the UFM1-ligase E3 enzyme UFL1 (PubMed:15071506, PubMed:20018847, PubMed:27653677, PubMed:29868776). Ufmyl

NucleusCytoplasm

Leukodystrophy, hypomyelinating, 14

An autosomal recessive, severe disorder characterized by atrophy of the basal ganglia and cerebellum, hypomyelination, severe developmental delay, typically without intentional movements and language development, and microcephaly. Almost all patients exhibit spasticity, extrapyramidal movement abnormalities, and severe drug-resistant epilepsy. Disease onset is early in infancy, and most patients die in the first years of life.

Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine (PubMed:8281145, PubMed:8399327). Enzyme with very low activity responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon (PubMed:8281145, PubMed:8399327)

Lysosome

Krabbe disease

An autosomal recessive disorder characterized by insufficient catabolism of several galactolipids that are important for normal myelin production. Four clinical forms are recognized. The infantile form accounts for 90% of cases. It manifests before six months of age with irritability, spasticity, arrest of motor and mental development, and bouts of temperature elevation without infection. This is followed by myoclonic jerks of arms and legs, oposthotonus, hypertonic fits, and mental regression, which progresses to a severe decerebrate condition with no voluntary movements and death from respiratory infections or cerebral hyperpyrexia before 2 years of age. Cases with later onset present with unexplained blindness, weakness and sensorimotor peripheral neuropathy, mental deterioration and death.

E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX10 also regula

Peroxisome membrane

Peroxisome biogenesis disorder complementation group 7

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor (PubMed:24235149, PubMed:28765278, PubMed:9653144). The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm (By similarity). Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion

Peroxisome membrane

Peroxisome biogenesis disorder complementation group K

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. May be involved in the binding of an intermediate of Fe/S cluster assembly

Mitochondrion

Multiple mitochondrial dysfunctions syndrome 4

A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death.

Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8 (PubMed:31778653). Cleaves preferentially single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides (PubMed:31778653, PubMed:38697119). In turn, RNase T2 degradation products promot

SecretedLysosome lumenEndoplasmic reticulum lumenMitochondrion intermembrane space

Leukoencephalopathy, cystic, without megalencephaly

An infantile-onset syndrome of cerebral leukoencephalopathy. Affected newborns develop microcephaly and neurologic abnormalities including psychomotor impairment, seizures and sensorineural hearing impairment. The brain shows multifocal white matter lesions, anterior temporal lobe subcortical cysts, pericystic abnormal myelination, ventriculomegaly and intracranial calcifications.

Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) (PubMed:11101887, PubMed:11336669, PubMed:12456682, PubMed:16314507, PubMed:17157249, PubMed:17428317, PubMed:21976670, PubMed:26344566, PubMed:7706321, PubMed:7719337, PubMed:7790377). Binds to cargo proteins containing a PTS1 peroxisomal targeting signal in the cytosol, and translocates them into the peroxisome matrix by passing through the PEX13-PEX14 dock

Cytoplasm, cytosolPeroxisome matrix

Peroxisome biogenesis disorder 2A

A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.

Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids. Catalyzes the irreversible conversion of 5-formyltetrahydrofolate (5-FTHF) to yield 5,10-methenyltetrahydrofolate

Cytoplasm

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

An autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy, and characterized by microcephaly, short stature, severe global developmental delay, progressive spasticity, and epilepsy. Brain imaging shows delayed myelination, hypomyelination, enlarged ventricles, and cerebellar atrophy.

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). Also edits incorrectly charged tRNA(Ala) via its editing domain (PubMed:21549344). In presence of high levels of lactate, also acts as a protein lactyltransferase that mediates lactylation of lysine residues in target proteins, such as CGAS (PubMed:39322678). Acts as an inhibitor of cGAS/STING signaling by catalyzing lac

Mitochondrion

Combined oxidative phosphorylation deficiency 8

A mitochondrial disease characterized by a lethal infantile hypertrophic cardiomyopathy, generalized muscle dysfunction and some neurologic involvement. The liver is not affected.

Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. Synthesizes 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci (PubMed:20413673, PubMed:33558766). Pol III-mediated transcription cycle proceeds through transcription initiation, transcription elongation and transcription termination stages. During transcription initiation, Pol III is rec

NucleusCytoplasm, cytosol

Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism

An autosomal recessive neurodegenerative disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism.

One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems

Cell membraneCell junction, gap junction

Leukodystrophy, hypomyelinating, 2

An autosomal recessive hypomyelinating leukodystrophy with symptoms of Pelizaeus-Merzbacher disease. Clinically characterized by nystagmus, impaired motor development, ataxia, choreoathetotic movements, dysarthria, and progressive spasticity.

Plays a role in vesicle-mediated protein trafficking to lysosomal compartments including the endocytic membrane transport and autophagic pathways. Believed to act as a core component of the putative HOPS and CORVET endosomal tethering complexes which are proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The HOPS complex is proposed

EndosomeLate endosome membraneLysosome membraneEarly endosomeCytoplasmic vesicleCytoplasmic vesicle, autophagosomeCytoplasmic vesicle, clathrin-coated vesicle

Leukodystrophy, hypomyelinating, 12

An autosomal recessive neurologic disorder characterized by developmental delay, spasticity, truncal hypotonia, acquired microcephaly, intellectual disability with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination.

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.

Catalyzes the reversible conversion of ribose-5-phosphate to ribulose 5-phosphate and participates in the first step of the non-oxidative branch of the pentose phosphate pathway

Ribose 5-phosphate isomerase deficiency

An autosomal recessive inborn error of polyols metabolism characterized by highly elevated level of ribitol and arabitol in brain and body fluids. Clinical features include leukoencephalopathy, psychomotor retardation from early life, neurologic regression, and a mild sensorimotor neuropathy.

Required for peroxisome membrane biogenesis. May play a role in early stages of peroxisome assembly. Can recruit other peroxisomal proteins, such as PEX3 and PMP34, to de novo peroxisomes derived from the endoplasmic reticulum (ER). May function as receptor for PEX3

Peroxisome membrane

Peroxisome biogenesis disorder complementation group 9

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA ATPase complex is

Cytoplasm, cytosolPeroxisome membraneCell projection, cilium, photoreceptor outer segment

Peroxisome biogenesis disorder complementation group 4

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling (PubMed:24662292, PubMed:9354782, PubMed:9632816). The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane (By similarity). PEX12 also re

Peroxisome membrane

Peroxisome biogenesis disorder complementation group 3

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling (PubMed:11439091, PubMed:16314507, PubMed:16854980, PubMed:21362118, PubMed:29884772). Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel (PubMed:29884772). Extraction by the PEX1-PEX6 AAA A

Cytoplasm, cytosolPeroxisome membrane

Peroxisome biogenesis disorder complementation group 1

A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS).

Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation (PubMed:15885354, PubMed:15917256). In glia, associates and targets CLCN2 at astrocytic processes and myelinated fiber tracts where it may regulate transcellular chloride flux involved in neuron excitability (PubMed:22405205)

CytoplasmCell membrane

Megalencephalic leukoencephalopathy with subcortical cysts 2A

A neurodegenerative disorder characterized by infantile-onset macrocephaly and later onset of motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. The brain appears swollen on magnetic resonance imaging with white-matter abnormalities and subcortical cysts, in all stages of the disease.

Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast

Cell membrane

Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex gamma subunit (PubMed:25858979, PubMed:27023709, PubMed:31048492). Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is re

Cytoplasm, cytosol

Leukoencephalopathy with vanishing white matter 3

An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit (PubMed:25858979, PubMed:27023709, PubMed:31048492). Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed (Pub

Cytoplasm, cytosol

Leukoencephalopathy with vanishing white matter 2

An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit (PubMed:25858979, PubMed:27023709, PubMed:31048492). Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed (Pub

Cytoplasm, cytosol

Leukoencephalopathy with vanishing white matter 1

An autosomal recessive brain disease characterized by neurological features including progressive cerebellar ataxia, spasticity, and cognitive deficits. Brain imaging shows abnormal white matter that vanishes over time and is replaced by cerebrospinal fluid. Disease severity ranges from fatal infantile forms to adult forms without neurological deterioration. The disease is progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Death may occurs after a variable period after disease onset, usually following an episode of fever and coma. A subset of affected females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Probably functions as a 3'-phosphoadenylyl sulfate:adenosine 3',5'-bisphosphate antiporter at the Golgi membranes. Mediates the transport from the cytosol into the lumen of the Golgi of 3'-phosphoadenylyl sulfate/adenosine 3'-phospho 5'-phosphosulfate (PAPS), a universal sulfuryl donor for sulfation events that take place in that compartment

Golgi apparatus membrane

Leukodystrophy, hypomyelinating, 26, with chondrodysplasia

A form of hypomyelinating leukodystrophy, a group of heterogeneous disorders characterized by persistent deficit of myelin observed on brain imaging. HLD26 is an autosomal recessive form characterized by severe psychomotor delay, limited or absent speech, abnormal development of brain white matter, corpus callosum hypoplasia, and cerebral atrophy. Other features include pre- and postnatal growth retardation, chondrodysplasia, and early-onset scoliosis.