Motor required for the retrograde transport of Golgi vesicles to the endoplasmic reticulum. Has a microtubule plus end-directed motility

Cytoplasm, cytoskeleton

Spastic ataxia 2, autosomal recessive

A neurologic disorder characterized by cerebellar ataxia, dysarthria, and variable spasticity of the lower limbs. Cognition is not affected.

Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates t

CytoplasmNucleusEndosome membraneCell membrane

Pituitary adenoma 4, ACTH-secreting

A form of pituitary adenoma, a neoplasm of the pituitary gland and one of the most common neuroendocrine tumors. Pituitary adenomas are clinically classified as functional and non-functional tumors, and manifest with a variety of features, including local invasion of surrounding structures and excessive hormone secretion. Functional pituitary adenomas are further classified by the type of hormone they secrete. PITA4 results in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes.

Displays arylsulfatase activity at neutral pH, when co-expressed with SUMF1; arylsulfatase activity is measured in the secretion medium of retinal cell line, but no activity is recorded when measured in cell extracts (PubMed:19262745). Lacks arylsulfatase activity (PubMed:16500042)

SecretedEndoplasmic reticulum

Regulator of deubiquitinating complexes, which acts as a strong activator of USP1, USP12 and USP46 (PubMed:18082604, PubMed:19075014, PubMed:26388029, PubMed:31253762). Enhances the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself (PubMed:18082604, PubMed:31253762). Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate (PubMed:19075014, PubMed:27373336). Also activates deubiquiti

NucleusCytoplasmLysosomeLate endosome

Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain (Probable). ATP synthase complex consist of a soluble F(1) head domain - the catalytic core - and a membrane F(1) domain - the membrane proton channel (PubMed:37244256). These two domains are linked by a central stalk rotating inside the F(1

Mitochondrion inner membrane

Neuropathy, ataxia, and retinitis pigmentosa

A syndrome characterized by variable combination of developmental delay, psychomotor retardation, hearing loss, optic atrophy and retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy.

Probable cytoskeleton-associated protease required for normal muscle growth. Involved in function, maturation and stabilization of the neuromuscular junction. May act by cleaving muscle-specific proteins such as FLNC (By similarity)

Cytoplasm, cytoskeletonCytoplasm, myofibril, sarcomere, Z line

Myopathy, myofibrillar, 7

A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM7 is an autosomal recessive form, clinically characterized by early childhood onset of slowly progressive muscle weakness and mild atrophy primarily affecting the lower limbs, associated with joint contractures.

Catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis (PubMed:15337768, PubMed:15863841, PubMed:17355976, PubMed:22517924). FA2H is stereospecific for the production of (R)-2-hydroxy fatty acids (PubMed:22517924). Plays an essential role in the synthesis of galactosphingolipids of the myelin sheath (By similarity). Responsible for the synthesis o

Endoplasmic reticulum membraneMicrosome membrane

Spastic paraplegia 35, autosomal recessive, with or without neurodegeneration

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. SPG35 is a complicated form characterized by childhood onset of gait difficulties. It has a rapid progression and many patients become wheelchair-bound as young adults. Patients manifest cognitive decline associated with leukodystrophy. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur.

Regulatory subunit of the Rab3 GTPase-activating (Rab3GAP) complex composed of RAB3GAP1 and RAB3GAP2, which accelerates the otherwise slow GTP hydrolysis catalyzed by Rab proteins (PubMed:9733780, PubMed:39779760). The complex has GTPase-activating protein (GAP) activity towards various Rab3 subfamily members (RAB3A, RAB3B, RAB3C and RAB3D), RAB5A and RAB43, and has guanine nucleotide exchange factor (GEF) activity towards RAB18 (PubMed:9733780, PubMed:39779760, PubMed:24891604). The Rab3GAP com

CytoplasmEndoplasmic reticulum

Martsolf syndrome 1

An autosomal recessive disease characterized by congenital cataracts, intellectual disability, and hypogonadism.

Ethanolaminephosphotransferase that catalyzes the transfer of phosphoethanolamine (PE) from CDP-ethanolamine to lipid acceptors, the final step in the synthesis of PE via the 'Kennedy' pathway (PubMed:17132865, PubMed:28052917, PubMed:29500230). PE is the second most abundant phospholipid of membranes in mammals and is involved in various membrane-related cellular processes (PubMed:17132865). The enzyme is critical for the synthesis of several PE species and also catalyzes the synthesis of plasm

Endoplasmic reticulum membrane

Spastic paraplegia 81, autosomal recessive

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. SPG81 is a complicated form characterized by white matter abnormalities, hypomyelination with progressive white matter loss, delayed motor development, progressive spasticity, and impaired intellectual development and speech delay. Additional features may include bifid uvula, microcephaly, seizures, and variable ocular anomalies.

GPI inositol-deacylase that catalyzes the remove of the acyl chain linked to the 2-OH position of inositol ring from the GPI-anchored protein (GPI-AP) in the endoplasmic reticulum (PubMed:24784135, PubMed:38167496). Initiates the post-attachment remodeling phase of GPI-AP biogenesis and participates in endoplasmic reticulum (ER)-to-Golgi transport of GPI-anchored protein (PubMed:24784135, PubMed:38167496)

Endoplasmic reticulum membrane

Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities

An autosomal recessive disorder characterized by severely delayed global development, with hypotonia, impaired intellectual development, and poor or absent speech. Most patients have spasticity with limb hypertonia and brisk tendon reflexes. Additional features include non-specific dysmorphic facial features, structural brain abnormalities, and cortical visual impairment.

Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1 (PubMed:17502376, PubMed:19240031). Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex (PubMed:21343306). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex (PubMe

Endoplasmic reticulum membrane

Spastic paraplegia 18B, autosomal recessive

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. SPG18B is a severe form with onset in early childhood. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures.

Plays a role in fibroblast growth factor-mediated signaling cascades that lead to the activation of MAP kinases. Promotes neurite outgrowth via FGFR1-mediated activation of downstream MAP kinases. Promotes an increase both in neurite number and in neurite length. May play a role in cell-cell adhesion and cell guidance via its interaction with ADGRL1/LPHN1 and ADGRL3

Cell membraneEndoplasmic reticulum membraneCytoplasmic vesicle membraneCytoplasm, perinuclear regionCell junction, focal adhesionSecretedCell projection, neuron projectionCell junction

Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and

Cytoplasm, cytosolEndoplasmic reticulumNucleusCytoplasm, Stress granule

Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1

An autosomal dominant disease characterized by disabling muscle weakness clinically resembling to limb girdle muscular dystrophy, osteolytic bone lesions consistent with Paget disease, and premature frontotemporal dementia. Clinical features show incomplete penetrance.

E3 ubiquitin-protein ligase involved in Golgi membrane fusion and regulation of small GTPases (PubMed:15254018, PubMed:21988917, PubMed:22036506, PubMed:37537642, PubMed:38332367). Acts as a regulator of Golgi membrane dynamics during the cell cycle: recruited to Golgi membrane by Rab proteins and regulates postmitotic Golgi membrane fusion (PubMed:21988917). Acts by mediating ubiquitination during mitotic Golgi disassembly, ubiquitination serving as a signal for Golgi reassembly later, after ce

Golgi apparatus, Golgi stack membraneCytoplasmEndoplasmic reticulum

ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine (PubMed:31996848). Also stimulates cellular uptake of polyamines and protects against polyamine toxicity (PubMed:31996848). Plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity (PubMed:22186024). Contributes to cellular zinc homeostasis (PubMed:24603074). Confers cellular protection against Mn(2+) and Zn(2+) toxicity and mitochondrial stress (PubMed:26134396). Required for pr

Lysosome membraneLate endosome membraneEndosome, multivesicular body membraneCytoplasmic vesicle, autophagosome membrane

Kufor-Rakeb syndrome

A rare form of autosomal recessive juvenile or early-onset, levodopa-responsive parkinsonism. In addition to typical parkinsonian signs, clinical manifestations of Kufor-Rakeb syndrome include behavioral problems, facial tremor, pyramidal tract dysfunction, supranuclear gaze palsy, and dementia.

May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport

Cytoplasm, cytosolNucleusCell projection, axonCell projection, dendrite

Spastic paraplegia 11, autosomal recessive

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.

AMP deaminase plays a critical role in energy metabolism. Catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle

Pontocerebellar hypoplasia 9

A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH9 features include severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy, thin corpus callosum, and delayed myelination.

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.

Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis (PubMed:25467444, PubMed:36493755, PubMed:35449234, PubMed:37193829). The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance (PubMed:25467444). As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cil

CytoplasmCytoplasm, cytoskeleton, microtubule organizing center, centrosome

Neuropathy, hereditary sensory, with spastic paraplegia, autosomal recessive

A disease characterized by spastic paraplegia and progressive distal sensory neuropathy leading to mutilating ulcerations of the upper and lower limbs.

Mitochondrial protein involved in the maturation of mitochondrial [4Fe-4S]-proteins in the late stage of the iron-sulfur cluster assembly pathway (PubMed:22323289, PubMed:23462291). Operates in cooperation with ISCA2 in the maturation of [4Fe-4S] proteins (PubMed:30269484) Involved in the maturation of mitochondrial 2Fe-2S proteins in the late stage of the iron-sulfur cluster assembly pathway

Mitochondrion

Multiple mitochondrial dysfunctions syndrome 3

A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. Some patients show failure to thrive, pulmonary hypertension, hypotonia and irritability. Biochemical features include severe combined deficiency of the 2-oxoacid dehydrogenases, defective lipoic acid synthesis and reduction in activity of mitochondrial respiratory chain complexes.

MitochondrionMitochondrion membraneEndoplasmic reticulumCytoplasm, cytosol

Neurodegeneration with brain iron accumulation 4

A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. NBIA4 results in speech difficulty, extrapyramidal signs, oromandibular and generalized dystonia, and parkinsonism. Most patients have progressive involvement of the corticospinal tract, with spasticity, hyperreflexia, and extensor plantar responses.

Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules (PubMed:23479643, PubMed:27813252). Required for secretory cargo traffic from the endoplasmic reticulum to the Golgi apparatus (PubMed:21478858)

Endoplasmic reticulum

Phosphatidylserine (PS) lipase that mediates the hydrolysis of phosphatidylserine to generate lysophosphatidylserine (LPS) (By similarity). LPS constitutes a class of signaling lipids that regulates immunological and neurological processes (By similarity). Has no activity towards diacylglycerol, triacylglycerol or lysophosphatidylserine lipase (PubMed:25290914). Also has monoacylglycerol lipase activity, with preference for 1-(9Z,12Z-octadecadienoyl)-glycerol (1-LG) and 2-glyceryl-15-deoxy-Delta

Membrane

Spastic paraplegia 86, autosomal recessive

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. SPG86 is an autosomal recessive form associated with impaired intellectual development, poor or absent speech, and behavioral abnormalities. Brain imaging shows thin corpus callosum and white matter abnormalities. Rare patients may have seizures.

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 (PubMed:11714285). Plays a role in the synthesis of ribosomal RNA in the nucleolus (PubMed:10791971)

Cytoplasm, cytosolNucleus, nucleolus

Interstitial lung and liver disease

An autosomal recessive, life-threatening disorder characterized by respiratory insufficiency and progressive liver disease with onset in infancy or early childhood. Clinical features include failure to thrive, hypotonia, intermittent lactic acidosis, aminoaciduria, hypothyroidism, interstitial lung disease, pulmonary alveolar proteinosis, anemia, and liver canalicular cholestasis, steatosis, and iron deposition.

Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies. May be involved in cell growth and differentiation

Late endosome membraneNucleus

Spastic paraplegia 53, autosomal recessive

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. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG53 is characterized by pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis.

Kinesin is a microtubule-associated force-producing protein that plays a role in organelle transport. The light chain functions in coupling of cargo to the heavy chain or in the modulation of its ATPase activity (Probable). Through binding with PLEKHM2 and ARL8B, recruits kinesin-1 to lysosomes and hence direct lysosomes movement toward microtubule plus ends (PubMed:22172677)

Cytoplasm, cytoskeletonLysosome membrane

Spastic paraplegia, optic atrophy, and neuropathy

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. SPOAN is characterized by spastic paraplegia with progressive joint contractures and spine deformities, loss of independent ambulation by age 10 years, sub-normal vision secondary to congenital optic atrophy, and neuropathy. Inheritance is autosomal recessive.

Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation (PubMed:33243891). As heterodimer with MTRES1, ejects the unfinished nascent chain and peptidyl transfer RNA (tRNA), respectively, from stalled ribosomes. Recruitment of mitoribosome biogenesis factors to these quality control intermediates suggests additional roles for MTRES1 and MTRF during mitoribosome rescue (PubMed:33243891)

Mitochondrion

Combined oxidative phosphorylation deficiency 7

A mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness.

E3 ubiquitin-protein ligase that plays an essential role in stimulus-induced inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) ubiquitination and degradation via the endoplasmic reticulum-associated degradation (ERAD) pathway. Also involved in ITPR1 turnover in resting cells. Selectively inhibits the TLR3-triggered innate immune response by promoting the 'Lys-48'-linked polyubiquitination and degradation of TLR3 (PubMed:31076723)

Endoplasmic reticulum membrane

Ataxia, sensory, 1, autosomal dominant

A rare disease characterized by progressive ataxia caused by degeneration of the posterior columns of the spinal cord. Affected individuals have a reduced ability to feel pain, temperature and vibration, particularly in the hands and feet. Their most prominent feature is an ataxic gait resulting from a severe loss of proprioception. Thus, patients rely on visual cues for maintaining proper body posture, such that they are unable to remain upright if their eyes are closed (Romberg sign).

Adhesion molecule that mediates interactions between myelinating cells and neurons by binding to neuronal sialic acid-containing gangliosides and to the glycoproteins RTN4R and RTN4RL2 (By similarity). Not required for initial myelination, but seems to play a role in the maintenance of normal axon myelination. Protects motoneurons against apoptosis, also after injury; protection against apoptosis is probably mediated via interaction with neuronal RTN4R and RTN4RL2. Required to prevent degenerati

Cell membraneMembrane raft

Spastic paraplegia 75, autosomal recessive

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. SPG75 is characterized by onset in early childhood and is associated with mild to moderate cognitive impairment.

Catalyzes the hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs) (Probable) (PubMed:8529670, PubMed:8626624, PubMed:8955160, PubMed:8996251). The enzyme sequentially removes phosphate groups in two successive steps, converting NTPs to nucleoside monophosphates (NMPs) via NDP intermediates (Probable) (PubMed:8529670, PubMed:8626624, PubMed:8955160, PubMed:8996251). This activity contributes to the regulation of extracellular levels of nucleotides (Probable) (PubMed:8529670, Pub

MembraneMembrane, caveola

Spastic paraplegia 64, autosomal recessive

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.

Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine) (PubMed:17105727, PubMed:30308956, PubMed:32144204). GlcCers are membrane glycosphingolipids that have a wide intracellular distribution (By similarity). They are the main precursors of more complex glycosphingolipids that play a role in cellular growth, differentiation, adhesion, signaling

Endoplasmic reticulum membraneGolgi apparatus membrane

Spastic paraplegia 46, autosomal recessive

A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging.

Broad specificity cytosolic 5'-nucleotidase that catalyzes the dephosphorylation of 6-hydroxypurine nucleoside 5'-monophosphates (PubMed:10092873, PubMed:12907246, PubMed:1659319, PubMed:9371705). In addition, possesses a phosphotransferase activity by which it can transfer a phosphate from a donor nucleoside monophosphate to an acceptor nucleoside, preferably inosine, deoxyinosine and guanosine (PubMed:1659319, PubMed:9371705). Has the highest activities for IMP and GMP followed by dIMP, dGMP a

Cytoplasm, cytosol

Spastic paraplegia 45, autosomal recessive

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. Some SPG45 patients manifest intellectual disability, contractures and learning disability.

Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation (PubMed:23862974, PubMed:28157540). Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death (PubMed:15178406). In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types (PubMed:28157540)

CytoplasmCell membraneApical cell membraneBasolateral cell membraneCell junction

Congenital anomalies of the kidney and urinary tract 1

A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children.

Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate

Neurodevelopmental disorder with spastic paraplegia and microcephaly

An autosomal recessive syndrome characterized by severe psychomotor developmental delay, dysarthria, walking difficulties, moderately to severely impaired intellectual development, poor or absent speech, and progressive microcephaly.

Positively regulates SLC1A1/EAAC1-mediated glutamate transport by increasing its affinity for glutamate in a PKC activity-dependent manner. Promotes the catalytic efficiency of SLC1A1/EAAC1 probably by reducing its interaction with ARL6IP5, a negative regulator of SLC1A1/EAAC1-mediated glutamate transport (By similarity). Plays a role in the formation and stabilization of endoplasmic reticulum tubules (PubMed:24262037). Negatively regulates apoptosis, possibly by modulating the activity of caspa

Endomembrane systemEndoplasmic reticulum membraneEndoplasmic reticulum

Spastic paraplegia 61, autosomal recessive

A complicated form of spastic paraplegia with polysensory and motor neuropathy. Spastic paraplegia is 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.

Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors. During brain development, critical in multiple processes, including neuronal migration, axonal growth and fasciculation, and synaptogenesis. In the mature brain, plays a role in the dynamics of neuronal structure and function, including synaptic plasticity

Cell membraneCell projection, growth coneCell projection, axonCell projection, dendrite

Hydrocephalus, congenital, X-linked

An X-linked recessive form of congenital hydrocephalus, a disease characterized by in utero onset of enlarged ventricles due to accumulation of ventricular cerebrospinal fluid. HYCX is the most common inherited form and occurs in approximately 1/30000 male births. The primary diagnostic criteria of intellectual disability and enlarged cerebral ventricles are often accompanied by spastic paraparesis and adducted thumbs and, occasionally, visual defects or seizures. The most severe cases die pre- or perinatally with gross hydrocephalus and enlarged head circumference. Stenosis of the aqueduct of Sylvius is frequently associated with the disorder.

Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism. Provides a docking site for the CRKL-C3G complex, resulting in Rap1-dependent sustained ERK activation. May play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EPHA4. In cooperation with SNTA1 can enhance EPHA4-induced JAK/STAT activation. Plays a role in nerve growth factor (NGF)-induced r

MembraneLate endosome

Spastic paraplegia, intellectual disability, nystagmus, and obesity

An autosomal dominant syndrome characterized by rapid growth in infancy, obesity, global developmental delay, intellectual disability, spastic paraplegia, ocular defects, and dysmorphic facial features.

Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate

CytoplasmCell membrane

Neurodevelopmental disorder with spasticity, hypomyelinating leukodystrophy, and brain abnormalities

A severe autosomal recessive disorder characterized by global developmental delay with impaired intellectual development and poor or absent speech, axial hypotonia, and peripheral spasticity and hyperreflexia. Brain imaging shows hypomyelination with decreased white matter volume, cerebral and cerebellar atrophy, and thin corpus callosum. Polymicrogyria may be observed in rare cases. Some patients have a primary immunodeficiency or gastrointestinal disturbances similar to inflammatory bowel disease.

Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction (PubMed:19617626, PubMed:21531719, PubMed:2400579). Proteolytically cleaves CTBP1 at 'Asn-375', 'Gly-387' and 'His-409' (PubMed:23707407). Cleaves and activates caspase-7 (CASP7) (PubMed:19617626)

CytoplasmCell membrane

Spastic paraplegia 76, autosomal recessive

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.

Diacylglycerol (DAG) and triacylglycerol (TAG) lipase required for proper lipid homeostasis in the central nervous system (PubMed:29278326, PubMed:37832604). It cooperates with PNPLA2/ATGL in neuronal TAG catabolism and hydrolyzes sn-1,3 DAG downstream of PNPLA2/ATGL (By similarity). In vitro, it also acts as a phospholipase that hydrolyzes preferentially phosphatidic acids, including 1,2-dioleoyl-sn-phosphatidic acid, phosphatidylcholine and phosphatidylethanolamine. Specifically binds to phosp

Cytoplasm, cytosolEndoplasmic reticulum-Golgi intermediate compartmentGolgi apparatus, cis-Golgi network

Spastic paraplegia 54, autosomal recessive

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. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG54 patients have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions, and an abnormal lipid peak due to accumulation of neutral lipids in certain brain regions.

Phosphatidylinositol 3-phosphate-binding protein required for the abscission step in cytokinesis: recruited to the midbody during cytokinesis and acts as a regulator of abscission. May also be required for efficient homologous recombination DNA double-strand break repair

Cytoplasm, cytoskeleton, microtubule organizing center, centrosomeMidbody

Spastic paraplegia 15, autosomal recessive

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. SPG15 is a complex form associated with additional neurological symptoms such as cognitive deterioration or intellectual disability, axonal neuropathy, mild cerebellar signs, and, less frequently, a central hearing deficit, decreased visual acuity, or retinal degeneration.

Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:19278620, PubMed:21533227, PubMed:30293840, PubMed:31708432). In association with LDAF1, defines the sites of LD formation in the ER (PubMed:31708432). Also required for growth and maturation of small nascent LDs into larger mature LDs (PubMed:27564575). Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts

Endoplasmic reticulum membraneLipid droplet

Lipodystrophy, congenital generalized, 2

A form of congenital generalized lipodystrophy, a metabolic disorder characterized by a near complete absence of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early onset of diabetes. Inheritance is autosomal recessive.

Lipophagy receptor that plays an important role in lipid droplet (LD) turnover in motor neurons (PubMed:37443287). Localizes to LDs and interacts with components of the autophagy machinery, such as MAP1LC3A/C proteins to deliver LDs to autophagosomes for degradation via lipophagy (PubMed:37443287). Lipid transfer protein required for lipid droplet degradation, including by lipophagy (PubMed:38190532). Can bind and transfer all lipid species found in lipid droplets, from phospholipids to triglyce

CytoplasmMidbodyLipid droplet

Spastic paraplegia 20, autosomal recessive

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. SPG20 is characterized by dysarthria, distal amyotrophy, mild developmental delay and short stature.

Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Catalyzes the hydrolysis of several naturally occurring membrane-associated lipids (PubMed:11927584). Hydrolyzes lysophospholipids and monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer. Does not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides (PubMed:11927584)

Endoplasmic reticulum membrane

Spastic paraplegia 39, autosomal recessive

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. SPG39 is associated with a motor axonopathy affecting upper and lower limbs and resulting in progressive wasting of distal upper and lower extremity muscles.

Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively

Golgi apparatus membrane

Spastic paraplegia 26, autosomal recessive

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. SPG26 is a complicated form characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive.

Bifunctional enzyme that converts glutamate to glutamate 5-semialdehyde, an intermediate in the biosynthesis of proline, ornithine and arginine

MitochondrionMitochondrion matrix

Cutis laxa, autosomal recessive, 3A

A syndrome characterized by facial dysmorphism with a progeroid appearance, large and late-closing fontanel, cutis laxa, joint hyperlaxity, athetoid movements and hyperreflexia, pre- and postnatal growth retardation, intellectual deficit, developmental delay, and ophthalmologic abnormalities.

Probably plays a role as positive regulator of autophagy

Neuropathy, hereditary sensory and autonomic, 9, with developmental delay

A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN9 is characterized by global developmental delay and intellectual disability, axial and appendicular hypotonia, dysarthria, and an abnormal gait that is often described as ataxic. Other features may include peripheral neuropathy, hyporeflexia, and autonomic dysfunction. Affected individuals also have dysmorphic features, thin corpus callosum on brain imaging, and episodes of central apnea, which may be fatal.