Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain. May catalyze the second step of the fatty acid remodeling, by reacylating a lyso-GPI intermediate at sn-2 of inositol phosphate by a saturated chain (By similarity). The fatty acid remodeling steps is critical for the integration of GPI-APs into lipid rafts (PubMed:23561846)

Golgi apparatus membrane

Hyperphosphatasia with impaired intellectual development syndrome 3

An autosomal recessive disorder usually characterized by intellectual disability, hypotonia with very poor motor development, poor speech, and increased serum alkaline phosphatase.

Key enzyme in triglyceride metabolism. Catalyzes the hydrolysis of triglycerides from circulating chylomicrons and very low density lipoproteins (VLDL), and thereby plays an important role in lipid clearance from the blood stream, lipid utilization and storage (PubMed:11342582, PubMed:27578112, PubMed:8675619). Although it has both phospholipase and triglyceride lipase activities it is primarily a triglyceride lipase with low but detectable phospholipase activity (PubMed:12032167, PubMed:7592706

Cell membraneSecretedSecreted, extracellular space, extracellular matrix

Hyperlipoproteinemia 1

An autosomal recessive metabolic disorder characterized by defective breakdown of dietary fats, impaired clearance of chylomicrons from plasma causing the plasma to have a milky appearance, and severe hypertriglyceridemia. On a normal diet, patients often present with abdominal pain, hepatosplenomegaly, lipemia retinalis, eruptive xanthomata, and massive hypertriglyceridemia, sometimes complicated with acute pancreatitis.

Component of chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) in plasma. Plays an important role in lipoprotein metabolism as an activator of lipoprotein lipase. Both proapolipoprotein C-II and apolipoprotein C-II can activate lipoprotein lipase. In normolipidemic individuals, it is mainly distributed in the HDL, whereas in hypertriglyceridemic individuals, predominantly found in the VLDL and LDL

Secreted

Hyperlipoproteinemia 1B

Autosomal recessive trait characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis.

APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids (PubMed:14754908, PubMed:1911868, PubMed:6860692). APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:14754908, PubMed:1911868, PubMed:1917954, PubMed:23620513, PubMed:2762297, PubMed:6860692, PubMed:9395455). Apolipoproteins are amphipathic mole

SecretedSecreted, extracellular spaceSecreted, extracellular space, extracellular matrixExtracellular vesicleEndosome, multivesicular body

Hyperlipoproteinemia 3

A disorder characterized by the accumulation of intermediate-density lipoprotein particles (IDL or broad-beta-lipoprotein) rich in cholesterol. Clinical features include xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause.

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

Rough endoplasmic reticulum membrane

Paroxysmal nocturnal hemoglobinuria 1

A disorder characterized by hemolytic anemia with hemoglobinuria, thromboses in large vessels, and a deficiency in hematopoiesis. Red blood cell breakdown with release of hemoglobin into the urine is manifested most prominently by dark-colored urine in the morning.

Alpha-1,6-mannosyltransferase that catalyzes the transfer of the second mannose, via an alpha-1,6 bond, from a dolichol-phosphate-mannose (Dol-P-Man) to a 2-acyl-6-(alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl)-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H2) intermediate to generate a 2-acyl-6-[alpha-D-mannosyl-(1->6)-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H3) and participates in the seventh step

Endoplasmic reticulum membrane

Hyperphosphatasia with impaired intellectual development syndrome 1

A severe syndrome characterized by elevated serum alkaline phosphatase, severe intellectual disability, seizures, hypotonia, facial dysmorphism, and hypoplastic terminal phalanges.

Acyltransferase that catalyzes the acyl transfer from an acyl-CoA at the 2-OH position of the inositol ring of a 6-(alpha-D-glucosaminyl)-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol (glucosaminyl phosphatidylinositol, GlcN-PI) to generate a 2-acyl-6-alpha-D-glucosaminyl-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol (glucosaminyl acyl phosphatidylinositol, GlcN-(acyl)PI) and participates in the fourth step of GPI-anchor biosynthesis (By similarity). Required for the transport of GPI

Endoplasmic reticulum membrane

Glycosylphosphatidylinositol biosynthesis defect 11

An autosomal recessive neurologic disorder characterized by developmental delay, intellectual disability, tonic seizures associated with hypsarrhythmia, dysmorphic facial features, and elevated serum alkaline phosphatase.

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.

Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (PubMed:11931631, PubMed:22057399, PubMed:25538232, PubMed:9090381). Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol (PubMed:11931631, PubMed:22057399, PubMed:25538232). Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, wh

Cytoplasm, cytosolPeroxisome matrix

Peroxisome biogenesis disorder complementation group 11

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).

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.

Catalyzes the deacylation of cholesteryl ester core lipids of endocytosed low density lipoproteins to generate free fatty acids and cholesterol (PubMed:15269241, PubMed:1718995, PubMed:7204383, PubMed:8112342, PubMed:9633819). Hydrolyzes triglycerides (1,2,3-triacylglycerol) and diglycerides (such as 1,2-diacylglycerol and 1,3-diacylglycerol) with preference for the acyl moieties at the sn-1 or sn-3 positions (PubMed:7204383, PubMed:8112342)

Lysosome

Cholesteryl ester storage disease

An autosomal recessive, mild form of lysosomal acid lipase deficiency characterized by accumulation of cholesteryl esters and triglycerides primarily in the liver. The clinical presentation is highly variable depending on residual levels of lysosomal acid lipase activity, and ranges from early onset of severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood. Age at onset varies from childhood to adulthood.

Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis (PubMed:11018465, PubMed:14570870, PubMed:24809814, PubMed:28165339). Required for global lipid homeostasis in liver and cholesterol homeostasis in fibroblasts. Involved in the regulation of pro-inflammatory response and neutrophil trafficking. Modulates neuronal autophagy via phosphoethanolamine production which r

Endoplasmic reticulum membrane

RENI syndrome

An autosomal recessive, steroid-resistant nephrotic syndrome that manifests in infancy or early childhood, and progresses to end-stage renal failure within a few years. Additional clinical features include ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects. In rare cases, patients present with isolated primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise.

Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain (PubMed:17021251, PubMed:24439110). May catalyze the first step of the fatty acid remodeling, by removing the unsaturated acyl chain at sn-2 of inositol phosphate, generating a lyso-GPI intermediate (Probable). The fatty acid remodeling steps is critical for the integration of GPI-APs into lipid rafts (By similarity)

Golgi apparatus membrane

Hyperphosphatasia with impaired intellectual development syndrome 4

An autosomal recessive neurologic disorder characterized by profound developmental delay, severe intellectual disability, no speech, psychomotor delay, postnatal microcephaly, and elevated serum alkaline phosphatase.

Catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol

Endoplasmic reticulum membrane

Coloboma, congenital heart disease, ichthyosiform dermatosis, impaired intellectual development, and ear anomalies syndrome

An extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, intellectual disability, and ear anomalies including conductive hearing loss. Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties.

Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-D-mannosyl-(1->2)-alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H6) intermediate to generate a a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-

Endoplasmic reticulum membrane

Hyperphosphatasia with impaired intellectual development syndrome 2

An autosomal recessive form of intellectual disability characterized by facial dysmorphism, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures.

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.

Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis (By similarity). Also plays a role in the regulation of the endocytic trafficking of EGFR (By similarity)

Endoplasmic reticulum membraneLipid droplet

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects

An X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, which typically results in male lethality. Clinically, it is characterized by congenital, unilateral, ichthyosisform erythroderma with striking lateralization, sharp midline demarcation, and ipsilateral limb defects and hypoplasia of the body. Limbs defects range from hypoplasia of digits or ribs to complete amelia, often including scoliosis.

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.

Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis (PubMed:11278915, PubMed:18302342, PubMed:9325256, PubMed:9392419)

CytoplasmPeroxisome

Mevalonic aciduria

Accumulation of mevalonic acid which causes a variety of symptoms such as psychomotor retardation, dysmorphic features, cataracts, hepatosplenomegaly, lymphadenopathy, anemia, hypotonia, myopathy, and ataxia.

Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that catalyzes the synthesis of very long chain saturated (VLC-SFA) and polyunsaturated (PUFA) fatty acids that are involved in multiple biological processes as precursors of membrane lipids and

Endoplasmic reticulum membrane

Stargardt disease 3

A form of Stargardt disease, a common hereditary macular degeneration characterized by decreased central vision, atrophy of the macula and underlying retinal pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD3 is an autosomal dominant form with onset most commonly in the second decade of life.

Oxidoreductase that catalyzes the last step of the cholesterol synthesis pathway, which transforms cholesta-5,7-dien-3beta-ol (7-dehydrocholesterol,7-DHC) into cholesterol by reducing the C7-C8 double bond of its sterol core (PubMed:25637936, PubMed:38297129, PubMed:38297130, PubMed:9465114, PubMed:9634533). Can also metabolize cholesta-5,7,24-trien-3beta-ol (7-dehydrodemosterol, 7-DHD) to desmosterol, which is then metabolized by the Delta(24)-sterol reductase (DHCR24) to cholesterol (By simila

Endoplasmic reticulum membrane

Smith-Lemli-Opitz syndrome

An autosomal recessive frequent inborn disorder of sterol metabolism with characteristic congenital malformations and intellectual disability. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and low serum cholesterol levels. SLOS occurs in relatively high frequency: approximately 1 in 20,000 to 30,000 births in populations of northern and central European background. Historically, a clinical distinction often was made between classic ('type I') SLOS and the more severely affected ('type II') patients. There is, in reality, a clinical and biochemical continuum from mild to severe SLOS.

Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries (By similarity). Anchors LPL on the surface of endothelial cells in the lumen of blood capillaries (By similarity). Protects LPL against loss of activity, and against ANGPTL4-mediated unfolding (PubMed:27929370, PubMed:29899144). Thereby, plays an important role in lipolytic processing of chylomicrons by LPL, triglyceride metabolism and lipid homeostasis (PubMed:1930457

Apical cell membraneBasolateral cell membraneCell membrane

Hyperlipoproteinemia 1D

An autosomal recessive disorder characterized by hyperlipoproteinemia, decreased plasma LPL levels in some patients, high plasma triglyceride levels, and refractory fasting chylomicronemia.

Could play a role in cell proliferation during neuronal differentiation and in protection against cell death

Endoplasmic reticulum membraneEndoplasmic reticulum-Golgi intermediate compartment membraneEndoplasmic reticulum

Ceroid lipofuscinosis, neuronal, 8

A form of neuronal ceroid lipofuscinosis with onset in childhood. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment patterns observed most often in neuronal ceroid lipofuscinosis type 8 comprise mixed combinations of granular, curvilinear, and fingerprint profiles.

Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans Has no beta-galactosidase catalytic activity, but plays functional roles in the formation of extracellular elastic fibers (elastogenesis) and in the development of connective tissue. Seems to be identical to the elastin-binding protein (EBP), a major component of the non-integrin cell surface receptor expressed on fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cance

LysosomeCytoplasm, perinuclear region

GM1-gangliosidosis 1

An autosomal recessive lysosomal storage disease marked by the accumulation of GM1 gangliosides, glycoproteins and keratan sulfate primarily in neurons of the central nervous system. GM1-gangliosidosis type 1 is characterized by onset within the first three months of life, central nervous system degeneration, coarse facial features, hepatosplenomegaly, skeletal dysmorphology reminiscent of Hurler syndrome, and rapidly progressive psychomotor deterioration. Urinary oligosaccharide levels are high. It leads to death usually between the first and second year of life.

Cytochrome P450 monooxygenase that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives. Hydroxylates (with R stereochemistry) the terminal methyl group of cholesterol side-chain in a three step reaction to yield at first a C26 alcohol, then a C26 aldehyde and finally a C26 acid (PubMed:12077124, PubMed:21411718, PubMed:28190002, PubMed:9660774). Regulates cholesterol homeostasis by catalyzing the conversion of excess cholesterol to bile acids via both the 'neutra

Mitochondrion inner membrane

Cerebrotendinous xanthomatosis

Rare sterol storage disorder characterized clinically by progressive neurologic dysfunction, premature atherosclerosis, and cataracts.

ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane (PubMed:27144356). Plays an essential role in the selective transport of dietary plant sterols and cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile (PubMed:11099417, PubMed:11138003, PubMed:15054092, PubMed:27144356). Required for normal sterol homeostasis (PubMed:11099417, PubMed:11138003, PubMed:15054092). The heter

Cell membraneApical cell membrane

Sitosterolemia 2

A form of sitosterolemia, an autosomal recessive metabolic disorder characterized by unregulated intestinal absorption of cholesterol, phytosterols and shellfish sterols, and decreased biliary excretion of dietary sterols into bile. Patients have hypercholesterolemia, very high levels of plant sterols in the plasma, and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease.

Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI biosynthesis (PubMed:16162815). May act by regulating the catalytic subunit PIGA (PubMed:16162815)

Endoplasmic reticulum membrane

Hyperphosphatasia with impaired intellectual development syndrome 6

An autosomal recessive, multisystem disorder characterized by severe developmental delay, dysmorphism, seizures, cataracts, and early death in some patients.

ABCG5 and ABCG8 form an obligate heterodimer that mediates Mg(2+)- and ATP-dependent sterol transport across the cell membrane. Plays an essential role in the selective transport of the dietary cholesterol in and out of the enterocytes and in the selective sterol excretion by the liver into bile (PubMed:11099417, PubMed:11452359, PubMed:15054092, PubMed:27144356). Required for normal sterol homeostasis (PubMed:11099417, PubMed:11452359, PubMed:15054092). The heterodimer with ABCG5 has ATPase act

Cell membraneApical cell membrane

Gallbladder disease 4

One of the major digestive diseases. Gallstones composed of cholesterol (cholelithiasis) are the common manifestations in western countries. Most people with gallstones, however, remain asymptomatic through their lifetimes.

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.

Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1',3'-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary for adequate mitochondrial function (PubMed:12930833, PubMed:19164547, PubMed:19700766, PubMed:26908608, PubMed:33096711). Its role in cellular physiology is to improve mitochondrial performance (PubMed:32234310). CL is critical for the coassembly of lipids and p

Mitochondrion outer membraneMitochondrion inner membraneMitochondrion membraneCytoplasm

Barth syndrome

An X-linked disease characterized by dilated cardiomyopathy with endocardial fibroelastosis, a predominantly proximal skeletal myopathy, growth retardation, neutropenia, and organic aciduria, particularly excess of 3-methylglutaconic acid. Additional features include hypertrophic cardiomyopathy, isolated left ventricular non-compaction, ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.

Lysophosphatidylserine (LPS) lipase that mediates the hydrolysis of lysophosphatidylserine, a class of signaling lipids that regulates immunological and neurological processes (PubMed:25290914, PubMed:30237167, PubMed:30420694, PubMed:30643283, PubMed:30720278). Represents a major lysophosphatidylserine lipase in the brain, thereby playing a key role in the central nervous system (By similarity). Also able to hydrolyze oxidized phosphatidylserine; oxidized phosphatidylserine is produced in respo

Endoplasmic reticulum membrane

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract

A slowly progressive neurologic disorder with a variable phenotype resembling Refsum disease. Clinical features include sensorineural hearing loss, visual problems related to cataracts, retinitis pigmentosa, pes cavus, ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features include hyporeflexia, hyperreflexia, extensor plantar responses.

Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane (PubMed:36264797). Catalyzes insertion of proteins with alpha-helical transmembrane regions, such as signal-anchored, tail-anchored and multi-pass membrane proteins (By similarity). Does not mediate insertion of beta-barrel transmembrane proteins (By similarity). May play a role in apoptosis (PubMed:12377771)

Mitochondrion outer membrane

Catalytic subunit of the ethanolamine phosphate transferase 2 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the second alpha-1,6-linked mannose of a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H7) intermediate to generate a 2-acyl-6-[6-phosphoethanolamine-

Endoplasmic reticulum membrane

Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy

An autosomal recessive disorder characterized by delayed psychomotor development, hypotonia, and early-onset seizures in most patients. Additional variable features are cerebellar atrophy, ataxia, and non-specific dysmorphic features. Some patients may have the Emm-null blood group phenotype.

Catalyzes the conversion of biologically active 11beta-hydroxyglucocorticoids (11beta-hydroxysteroid) such as cortisol, to inactive 11-ketoglucocorticoids (11-oxosteroid) such as cortisone, in the presence of NAD(+) (PubMed:10497248, PubMed:12788846, PubMed:17314322, PubMed:22796344, PubMed:27927697, PubMed:30902677, PubMed:33387577, PubMed:7859916, PubMed:8538347). Functions as a dehydrogenase (oxidase), thereby decreasing the concentration of active glucocorticoids, thus protecting the nonsele

MicrosomeEndoplasmic reticulum

Apparent mineralocorticoid excess

An autosomal recessive form of low-renin hypertension. It is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, hypernatremia, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis.