Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted d Involved in SSU pre-rRNA proce

Nucleus, nucleolusChromosome

Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17

Basolateral cell membraneBasal cell membrane

Hyperbilirubinemia, Rotor type

An autosomal recessive form of primary conjugated hyperbilirubinemia. Affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. They have delayed plasma clearance of the unconjugated anionic dye bromsulphthalein and prominent urinary excretion of coproporphyrin I. Hepatic pigmentation is normal.

Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins (PubMed:11689424, PubMed:18004775). Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme) (PubMed:11689424, PubMed:18004775)

Cytoplasm, cytosol

Congenital erythropoietic porphyria

Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. The manifestations of CEP are heterogeneous, ranging from nonimmune hydrops fetalis due to severe hemolytic anemia in utero to milder, later onset forms, which have only skin lesions due to cutaneous photosensitivity in adult life. The deficiency in UROS activity results in the non-enzymatic conversion of hydroxymethylbilane (HMB) into the uroporphyrinogen-I isomer.

Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroep

Cell membraneEndoplasmic reticulum membrane

Cholestasis, progressive familial intrahepatic, 6

An autosomal recessive form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease. PFIC6 patients have elevated liver transaminases and congenital diarrhea.

Key regulator of abscission step in cytokinesis: part of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage. Together with CHMP4C, required to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis. Deactivation of AURKB results in dephosphorylation of CHMP4C followed by its dissociation

Cytoplasm, cytoskeleton, microtubule organizing center, centrosomeCleavage furrowMidbody, Midbody ring

ATP-dependent transporter of the ATP-binding cassette (ABC) family that binds and hydrolyzes ATP to enable active transport of various substrates including many drugs, toxicants and endogenous compound across cell membranes. Transports a wide variety of conjugated organic anions such as sulfate-, glucuronide- and glutathione (GSH)-conjugates of endo- and xenobiotics substrates (PubMed:10220572, PubMed:10421658, PubMed:11500505, PubMed:16332456). Mediates hepatobiliary excretion of mono- and bis-

Apical cell membrane

Dubin-Johnson syndrome

Autosomal recessive disorder characterized by conjugated hyperbilirubinemia, an increase in the urinary excretion of coproporphyrin isomer I, deposition of melanin-like pigment in hepatocytes, and prolonged retention of sulfobromophthalein, but otherwise normal liver function.

Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron (PubMed:11121422, PubMed:19556236, PubMed:7703255). Affords protection against programmed cell death and this cytoprotective effect relies on its ability to catabolize free heme and prevent it from sensitizing cells to undergo apoptosis (PubMed:20055707) (Microbial infection) During SARS-COV-2

Endoplasmic reticulum membrane

Heme oxygenase 1 deficiency

A disease characterized by impaired stress hematopoiesis, resulting in marked erythrocyte fragmentation and intravascular hemolysis, coagulation abnormalities, endothelial damage, and iron deposition in renal and hepatic tissues. Clinical features include persistent hemolytic anemia, asplenia, nephritis, generalized erythematous rash, growth retardation and hepatomegaly.

Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, Pub

Apical cell membraneRecycling endosome membraneEndosomeCell membrane

Cholestasis, progressive familial intrahepatic, 2

A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. PFIC2 inheritance is autosomal recessive.

Deubiquitinase that mediates 'Lys-63'-linked deubiquitination of tight junction proteins, such as MARVELD2 and LSR, and which is involved in the survival of auditory hair cells and hearing (PubMed:32124521, PubMed:39587316). Specifically cleaves 'Lys-63'-linked polyubiquitin chains composed of at least 3 ubiquitin molecules, while it is not able to deubiquitinate substrates with shorter ubiquitin chains: recognizes ubiquitin chain in position S2 and catalyzes en bloc cleavage of polyubiquitin ch

Cell junction, tight junction

Cholestasis, progressive familial intrahepatic, 7, with or without hearing loss

An autosomal recessive form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease. Some PFIC7 patients develop hearing loss in childhood.

As part of the heme biosynthetic pathway, catalyzes the sequential polymerization of four molecules of porphobilinogen to form hydroxymethylbilane, also known as preuroporphyrinogen (PubMed:18004775, PubMed:18936296, PubMed:19138865, PubMed:23815679). Catalysis begins with the assembly of the dipyrromethane cofactor by the apoenzyme from two molecules of porphobilinogen or from preuroporphyrinogen. The covalently linked cofactor acts as a primer, around which the tetrapyrrole product is assemble

Cytoplasm, cytosol

Acute intermittent porphyria

A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AIP is an autosomal dominant form of hepatic porphyria characterized by attacks of gastrointestinal disturbances, abdominal colic, with neurological dysfunctions, hypertension, tachycardia and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.

Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX

Mitochondrion inner membrane

Variegate porphyria

A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Variegate porphyria is an acute hepatic form characterized by partial reduction of protoporphyrinogen oxidase activity, increased photosensitivity, skin blistering and scarring of sun-exposed areas, skin hyperpigmentation, abdominal pain, and neuropsychiatric symptoms. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. Inheritance is autosomal dominant with incomplete penetrance.

Serine/threonine protein kinase that may be involved in the regulation of pre-mRNA processing. It may phosphorylate components of nuclear splice factor compartments (SFC), such as non-snRNP splicing factors containing a serine/arginine-rich domain (SR proteins). Reversible phosphorylation of SR proteins may cause their release into the nucleoplasm and change their local concentration, thereby influencing alternative splicing

Golgi apparatusCytoplasm, cytoskeleton, microtubule organizing center, centrosomeNucleus speckleEndoplasmic reticulum membraneCell membraneCytoplasm

Cholestasis, progressive familial intrahepatic, 13

A form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease. PFIC13 is an autosomal recessive form characterized by progressive liver dysfunction and chronic renal failure often associated with unilateral renal agenesis and glomerulosclerosis.

May be involved in vesicular trafficking via its association with the CART complex. The CART complex is necessary for efficient transferrin receptor recycling but not for EGFR degradation. Required in a complex with RAB11A and RAB11FIP2 for the transport of NPC1L1 to the plasma membrane. Together with RAB11A participates in CFTR trafficking to the plasma membrane and TF (transferrin) recycling in nonpolarized cells. Together with RAB11A and RAB8A participates in epithelial cell polarization. Tog

Cytoplasm

Diarrhea 2, with microvillus atrophy, with or without cholestasis

A disease characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset microvillus inclusion disease with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life.

Plays an important role in integrin-mediated signaling and functions both in regulating cell migration and immune responses. Promotes formation of focal adhesion complexes, activation of the protein kinase PTK2/FAK1 and subsequent phosphorylation of MAPK1 and MAPK3. Promotes production of pro-inflammatory cytokines by monocytes and macrophages. Plays an important role in modulating inflammation and T-cell-mediated immune responses. Promotes axon growth in the embryonic olfactory bulb. Promotes a

Cell membrane

Cholestasis, progressive familial intrahepatic, 11

An autosomal recessive form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease.

Plays a role in tight junctions and adherens junctions (By similarity). Acts as a positive regulator of RANKL-induced osteoclast differentiation, potentially via mediating downstream transcriptional activity (By similarity)

Cell junction, adherens junctionCell membraneCell junction, tight junctionNucleus

Hypercholanemia, familial, 1

A disorder characterized by elevated serum bile acid concentrations, itching, and fat malabsorption.

Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen

Cytoplasm, cytosol

Acute hepatic porphyria

A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors.

Transcriptional activator or repressor which serves as a general switch factor for erythroid development (PubMed:35030251). It binds to DNA sites with the consensus sequence 5'-[AT]GATA[AG]-3' within regulatory regions of globin genes and of other genes expressed in erythroid cells. Activates the transcription of genes involved in erythroid differentiation of K562 erythroleukemia cells, including HBB, HBG1/2, ALAS2 and HMBS (PubMed:24245781)

Nucleus

X-linked dyserythropoietic anemia and thrombocytopenia

Disorder characterized by erythrocytes with abnormal size and shape, and paucity of platelets in peripheral blood. The bone marrow contains abundant and abnormally small megakaryocytes.

Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds

Nucleus

Proposed to be involved in endosomal maturation implicating in part VPS33B. In epithelial cells, the VPS33B:VIPAS39 complex may play a role in the apical RAB11A-dependent recycling pathway and in the maintenance of the apical-basolateral polarity (PubMed:20190753). May play a role in lysosomal trafficking, probably via association with the core HOPS complex in a discrete population of endosomes; the functions seems to be independent of VPS33B (PubMed:19109425). May play a role in vesicular traff

CytoplasmCytoplasmic vesicleEarly endosomeRecycling endosomeLate endosome

Arthrogryposis, renal dysfunction and cholestasis syndrome 2

A multisystem disorder, characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity. Platelet dysfunction is common.

UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867, PubMed:15231852, PubMed:21422672, PubMed:38211441). Essential for the elimination and detoxification of drugs, xenobiot

Endoplasmic reticulum membraneCytoplasm, perinuclear region

Gilbert syndrome

Occurs as a consequence of reduced bilirubin transferase activity and is often detected in young adults with vague non-specific complaints.

Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin

Cell membrane

Hemochromatosis 1

A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading.

Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane (PubMed:17948906, PubMed:25315773). May participate in the establishment of the canalicular membrane integrity by ensuring asymmetric distribution of phospholipids in the canicular membrane (By similarity). Thus may have a role in the regulation of bile acids transpo

Cell membraneApical cell membraneCell projection, stereociliumEndoplasmic reticulumGolgi apparatus

Cholestasis, progressive familial intrahepatic, 1

A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. PFIC1 inheritance is autosomal recessive.

ATP-dependent chaperone that functions as an unfoldase. As part of the ClpXP protease complex, it recognizes specific protein substrates, unfolds them using energy derived from ATP hydrolysis, and then translocates them to the proteolytic subunit (CLPP) of the ClpXP complex for degradation (PubMed:11923310, PubMed:22710082, PubMed:28874591). Thanks to its chaperone activity, it also functions in the incorporation of the pyridoxal phosphate cofactor into 5-aminolevulinate synthase, thereby activa

MitochondrionMitochondrion matrix, mitochondrion nucleoid

Protoporphyria, erythropoietic, 2

An autosomal dominant form of porphyria with onset in infancy. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Erythropoietic protoporphyria is marked by excessive protoporphyrin in erythrocytes, plasma, liver and feces, and by widely varying photosensitive skin changes ranging from a burning or pruritic sensation to erythema, edema and wheals.

Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion. Functions as a floppase that translocates specifically phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane bilayer into the canaliculi of hepatocytes. Translocation of PC makes the biliary phospholipids available for extraction into the canaliculi lumen by bile salt mixed micelles and therefore protects the biliary tree from the detergent activity o

Cell membraneApical cell membraneMembrane raftCytoplasmCytoplasmic vesicle, clathrin-coated vesicle

Cholestasis, progressive familial intrahepatic, 3

A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. PFIC3 inheritance is autosomal recessive.

Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-th

Basolateral cell membraneBasal cell membrane

Hyperbilirubinemia, Rotor type

An autosomal recessive form of primary conjugated hyperbilirubinemia. Affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. They have delayed plasma clearance of the unconjugated anionic dye bromsulphthalein and prominent urinary excretion of coproporphyrin I. Hepatic pigmentation is normal.

Involved in the negative regulation of fatty acid biosynthesis, probably acting as an adapter that allows ubiquitination of acetyl-CoA carboxylase 1 (ACACA) by E3 ubiquitin-protein ligase COP1, and promotes ACACA degradation (PubMed:39920308). The adapter function requires the C-terminal proline-rich domain and may be apart from the kinesin motor activity (Probable)

Cytoplasm, cytoskeletonCell projection, cilium

Cholestasis, progressive familial intrahepatic, 8

An autosomal recessive form of progressive cholestasis, a disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease. PFIC8 onset is in early infancy.

Catalyzes the sequential decarboxylation of the four acetate side chains of uroporphyrinogen to form coproporphyrinogen and participates in the fifth step in the heme biosynthetic pathway (PubMed:11069625, PubMed:11719352, PubMed:14633982, PubMed:18004775, PubMed:21668429). Isomer I or isomer III of uroporphyrinogen may serve as substrate, but only coproporphyrinogen III can ultimately be converted to heme (PubMed:11069625, PubMed:11719352, PubMed:14633982, PubMed:21668429). In vitro also decarb

Cytoplasm, cytosol

Familial porphyria cutanea tarda

A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Familial porphyria cutanea tarda is an autosomal dominant disorder characterized by light-sensitive dermatitis, with onset in later life. It is associated with the excretion of large amounts of uroporphyrin in the urine. Iron overload is often present in association with varying degrees of liver damage.

May play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes. Required for proper trafficking and targeting of the collagen-modifying enzyme lysyl hydroxylase 3 (LH3) to intracellular collagen (PubMed:28017832). Mediates phagolysosomal fusion in macrophages (PubMed:18474358). Proposed to be involved in endosomal maturation implicating VIPAS39. In epithelial cells, the VPS33B:VIPAS39 complex may play a role

Late endosome membraneLysosome membraneEarly endosomeCytoplasmic vesicle, clathrin-coated vesicleRecycling endosome

Arthrogryposis, renal dysfunction, and cholestasis 1

An autosomal recessive multisystem disorder with characteristics of congenital joint contractures, renal tubular dysfunction, neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase activity, severe failure to thrive, ichthyosis, and a defect in platelet alpha-granule biogenesis. Most patients do not survive past the first year of life.

Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products (PubMed:14643893, PubMed:21252495, PubMed:21309041, PubMed:21653323, PubMed:32499479, PubMed:34492704). Contributes significantly to heme formation during erythropoiesis (PubMed:2050125) Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-

Mitochondrion inner membrane

Anemia, sideroblastic, 1

A form of sideroblastic anemia that shows a variable hematologic response to pharmacologic doses of pyridoxine. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus.

Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway

Mitochondrion inner membrane

Protoporphyria, erythropoietic, 1

An autosomal recessive form of porphyria with onset usually before age 10 years. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Erythropoietic protoporphyria is marked by excessive protoporphyrin in erythrocytes, plasma, liver and feces, and by widely varying photosensitive skin changes ranging from a burning or pruritic sensation to erythema, edema and wheals.

Catalyzes the aerobic oxidative decarboxylation of propionate groups of rings A and B of coproporphyrinogen-III to yield the vinyl groups in protoporphyrinogen-IX and participates to the sixth step in the heme biosynthetic pathway

Mitochondrion intermembrane space

Hereditary coproporphyria

A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Hereditary coproporphyria is an acute hepatic porphyria characterized by skin photosensitivity, attacks of abdominal pain, neurological disturbances, and psychiatric symptoms. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. Hereditary coproporphyria is biochemically characterized by overexcretion of coproporphyrin III in the urine and in the feces.