Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin

Cell membrane

Glycogen storage disease 9A

A metabolic disorder resulting in a mild liver glycogenosis with clinical symptoms that include hepatomegaly, growth retardation, muscle weakness, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis. Two subtypes are known: type 1 or classic type with no phosphorylase kinase activity in liver or erythrocytes, and type 2 or variant type with no phosphorylase kinase activity in liver, but normal activity in erythrocytes. Unlike other glycogenosis diseases, glycogen storage disease type 9A is generally a benign condition. Patients improve with age and are often asymptomatic as adults. Accurate diagnosis is therefore also of prognostic interest.

Pyruvate carboxylase catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second. Catalyzes in a tissue specific manner, the initial reactions of glucose (liver, kidney) and lipid (adipose tissue, liver, brain) synthesis from pyruvate

Mitochondrion matrix

Pyruvate carboxylase deficiency

Leads to lactic acidosis, intellectual disability and death. It occurs in three forms: mild or type A, severe neonatal or type B, and a very mild lacticacidemia.

Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase. Generates alpha-1,6-glucosidic branches from alpha-1,4-linked glucose chains, to increase solubility of the glycogen polymer (PubMed:26199317, PubMed:8463281, PubMed:8613547)

Glycogen storage disease 4

A metabolic disorder characterized by the accumulation of an amylopectin-like polysaccharide. The typical clinical manifestation is liver disease of childhood, progressing to lethal hepatic cirrhosis. Most children with this condition die before two years of age. However, the liver disease is not always progressive. No treatment apart from liver transplantation has been found to prevent progression of the disease. There is also a neuromuscular form of glycogen storage disease type 4 that varies in onset (perinatal, congenital, juvenile, or adult) and severity.

Catalyzes the removal of sialic acid (N-acetylneuraminic acid) moieties from glycoproteins and glycolipids. To be active, it is strictly dependent on its presence in the multienzyme complex. Appears to have a preference for alpha 2-3 and alpha 2-6 sialyl linkage

Lysosome membraneLysosome lumenCell membraneCytoplasmic vesicleLysosome

Sialidosis

Lysosomal storage disease occurring as two types with various manifestations. Type 1 sialidosis (cherry red spot-myoclonus syndrome or normosomatic type) is late-onset and it is characterized by the formation of cherry red macular spots in childhood, progressive debilitating myoclonus, insiduous visual loss and rarely ataxia. The diagnosis can be confirmed by the screening of the urine for sialyloligosaccharides. Type 2 sialidosis (also known as dysmorphic type) occurs as several variants of increasing severity with earlier age of onset. It is characterized by the presence of abnormal somatic features including coarse facies and dysostosis multiplex, vertebral deformities, intellectual disability, cherry-red spot/myoclonus, sialuria, cytoplasmic vacuolation of peripheral lymphocytes, bone marrow cells and conjunctival epithelial cells.

Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids

Lysosome

Schindler disease

Form of NAGA deficiency characterized by early-onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive.

Serine/threonine-protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Acts as a MAPK kinase kinase kinase (MAP4K) and is an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and to a lesser extent of the p38 MAPKs signaling pathway. Required for the efficient activation of JNKs by TRAF6-dependent stimuli, including pathogen-associated molecular patterns (PAMPs) such as polyinosine-polycytidi

CytoplasmBasolateral cell membraneGolgi apparatus membrane

Plays an important role in galactose metabolism

Galactosemia 1

A form of galactosemia, an inborn error of galactose metabolism typically manifesting in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. GALAC1 inheritance is autosomal recessive.

Inorganic phosphate and glucose-6-phosphate antiporter of the endoplasmic reticulum. Transports cytoplasmic glucose-6-phosphate into the lumen of the endoplasmic reticulum and translocates inorganic phosphate into the opposite direction (PubMed:33964207). Forms with glucose-6-phosphatase the complex responsible for glucose production through glycogenolysis and gluconeogenesis. Hence, it plays a central role in homeostatic regulation of blood glucose levels

Endoplasmic reticulum membrane

Glycogen storage disease 1B

A metabolic disorder characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Patients manifest a wide range of clinical symptoms and biochemical abnormalities, including hypoglycemia, severe hepatomegaly due to excessive accumulation of glycogen, kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. Glycogen storage disease type 1B patients also present a tendency towards infections associated with neutropenia, relapsing aphthous gingivostomatitis, and inflammatory bowel disease.

Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+)

Cytoplasm

Glycogen storage disease 11

A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.

Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport (PubMed:15510212, PubMed:21781115, PubMed:22778404, PubMed:23889254). Electroneutral proton-coupled acidic monosaccharide symporter, with a sugar to proton stoichiometry of 1:1. Exports glucuronic acid and free sialic acid derived from sialoglycoconjugate degradation out of lysosomes, driven by outwardly directed lysosomal

Basolateral cell membraneCytoplasmic vesicle, secretory vesicle, synaptic vesicle membraneLysosome membrane

Salla disease

Sialic acid storage disease (SASD). SASDs are autosomal recessive neurodegenerative disorders characterized by hypotonia, cerebellar ataxia and intellectual disability. They are caused by a defect in the metabolism of sialic acid which results in increased urinary excretion of unconjugated sialic acid, specifically N-acetylneuraminic acid. Enlarged lysosomes are seen on electron microscopic studies. Clinical symptoms of SD present usually at age less than 1 year and progression is slow.

Beta-1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAc-beta-1-3GlcNAc, on N- and O-glycans. Has no galactose nor galactosaminyl transferase activity toward any acceptor substrate. Involved in alpha-dystroglycan (DAG1) glycosylation: acts coordinately with GTDC2/POMGnT2 to synthesize a GalNAc-beta3-GlcNAc-beta-terminus at the 4-position of protein O-mannose in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3

Golgi apparatus membraneEndoplasmic reticulum

Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A11

An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound intellectual disability, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease.

Probably involved in connections of major cytoskeletal structures to the plasma membrane. In epithelial cells, required for the formation of microvilli and membrane ruffles on the apical pole. Along with PLEKHG6, required for normal macropinocytosis

Apical cell membraneCell projectionCell projection, microvillus membraneCell projection, ruffle membraneCytoplasm, cell cortexCytoplasm, cytoskeletonCell projection, microvillus

Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi

Golgi apparatus, cis-Golgi networkEndoplasmic reticulumCytoplasm

Intellectual developmental disorder, autosomal recessive 13

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Brain magnetic resonance imaging of MRT13 patients indicates the presence of mild cerebral white matter hypoplasia. Microcephaly is present in some but not all affected individuals.

Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; i

NucleusNucleus membraneNucleus envelopeNucleus, nuclear pore complexCytoplasmCytoplasm, cytoskeleton, spindleChromosome, centromere, kinetochore

Catalyzes the methylation of 5-carboxymethyl uridine to 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in tRNA via its methyltransferase domain (PubMed:20123966, PubMed:20308323, PubMed:31079898). Catalyzes the last step in the formation of 5-methylcarboxymethyl uridine at the wobble position of the anticodon loop in target tRNA (PubMed:20123966, PubMed:20308323). Has a preference for tRNA(Arg) and tRNA(Glu), and does not bind tRNA(Lys) (PubMed:20308323). Binds tRNA a

CytoplasmNucleus

Intellectual developmental disorder, autosomal recessive 71

A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT71 features include impaired intellectual development, global developmental delay, mildly delayed walking, poor language, seizures in the first years of life, and behavioral abnormalities.

Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary) (PubMed:37267905). The FERRY complex directly interacts with mRNAs and RAB5A, and functions as a RAB5A effector involved in the localization and the distribution of specific mRNAs most likely by mediating their endosomal transport. The complex recruits mRNAs and ribosomes to early endosomes through direct mRNA-interaction (PubMed:37267905). Plays a role in mast cell degranulation

CytoplasmEarly endosome

Intellectual developmental disorder, autosomal recessive 66

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT66 patients have intellectual disability, delayed speech development, neuropsychiatric symptoms, and relatively normal life span.

Required for ciliogenesis and for structural integrity at the ciliary tip

Cell projection, ciliumCytoplasm, cytoskeleton, microtubule organizing center, centrosome, centrioleCytoplasm, cytoskeleton, microtubule organizing center, centrosomeCytoplasm, cytoskeleton, spindle pole

Joubert syndrome 25

A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS25 clinical manifestations appear to be confined to the neurologic system. JBTS25 inheritance is autosomal recessive.

Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) leading to the production of a phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18094042, PubMed:18772128). Prefers arachidonoyl-CoA as the acyl donor, thus contributing to the regulation of free levels arachid

Endoplasmic reticulum membrane

Intellectual developmental disorder, autosomal recessive 57

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT57 patients have moderate to severe intellectual disability, and delayed psychomotor development with poor or absent speech. Some patients manifest seizures and autistic features.

E3 ubiquitin-protein ligase component of the LUBAC complex which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation (PubMed:17006537, PubMed:19136968, PubMed:20005846, PubMed:21455173, PubMed:21455180, PubMed:21455181, PubMed:22863777, PubMed:28189684, PubMed:28481331). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signal

Cytoplasm

Immunodeficiency 115 with autoinflammation

An autosomal recessive immunologic disorder manifesting in early infancy and characterized by combined immunodeficiency, recurrent bacterial, viral, and fungal infections, as well as autoinflammatory features, including arthritis and dermatitis.

Hydrolyzes 6-sulfate groups in N-acetyl-d-glucosaminide units of heparin sulfate and keratan sulfate

Lysosome

Mucopolysaccharidosis 3D

A form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life.

Together with PDHA1 forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex (PubMed:17474719, PubMed:19081061). The PDH complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3) (P

Mitochondrion matrix

Pyruvate dehydrogenase E1-beta deficiency

An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.

Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate, oxidizes D-glycerate to hydroxypyruvate

Hyperoxaluria primary 2

A disorder characterized by elevated urinary excretion of oxalate and L-glycerate, progressive tissue accumulation of insoluble calcium oxalate, nephrolithiasis, nephrocalcinosis, and end-stage renal disease.

Catalyzes the transfer of a phosphate from ATP to alpha-D-galactose and participates in the first committed step in the catabolism of galactose

Galactosemia 2

A form of galactosemia, an inborn error of galactose metabolism typically manifesting in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. GALAC2 inheritance is autosomal recessive.

Magnesium-independent polyisoprenoid diphosphatase that catalyzes the sequential dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates (PubMed:16464866, PubMed:19220020, PubMed:20110354). Functions in the innate immune response through the dephosphorylation of presqualene diphosphate which acts as a potent inhibitor of the signaling pathways contributing to polymorphonuclear neutrophils activation (PubMed:16464866, PubMed:23568778). May regulate the biosynthesis of

Endoplasmic reticulum membraneNucleus envelopeNucleus inner membrane

The pyruvate dehydrogenase (PDH) complex, catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (Probable). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3); (Probable). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme

Mitochondrion matrix

Catalyzes a step in lysosomal heparan sulfate degradation

Lysosome

Mucopolysaccharidosis 3A

A severe form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life. MPS3A is characterized by earlier onset, rapid progression of symptoms and shorter survival.

Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defe

CytoplasmNucleusNucleus, nucleolusNucleus, nucleoplasm

Pontocerebellar hypoplasia 1D

An autosomal recessive neurologic disorder with onset at birth or in infancy, and characterized by progressive axonal motor neuronopathy, severe generalized hypotonia, respiratory insufficiency, and cerebellar atrophy. Death in childhood may occur.

Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response (PubMed:14645249, PubMed:18617507, PubMed:19103756, PubMed:33076429). Controls chromatin organization and remodeling by mediating phosphorylation of histone H3 on 'Thr-4' and histone H2AX (H2aXT4ph) (PubMed:31527692, PubMed:37179361). It also phosphorylates KAT5 in response to DNA damage, promoting KAT5 association with chr

NucleusCytoplasmNucleus, Cajal body

Pontocerebellar hypoplasia 1A

A form of pontocerebellar hypoplasia, a disorder characterized by structural defects of the pons and cerebellum, evident upon brain imaging. PCH1A is an autosomal recessive form characterized by an abnormally small cerebellum and brainstem, central and peripheral motor dysfunction from birth, gliosis and spinal cord anterior horn cells degeneration resembling infantile spinal muscular atrophy. Additional features include muscle hypotonia, congenital contractures and respiratory insufficiency that is evident at birth.

Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defe

CytoplasmNucleusNucleus, nucleolus

Pontocerebellar hypoplasia 1C

A severe autosomal recessive neurodegenerative disease characterized by cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system, and spinal motor neuron disease. Affected individuals manifest failure to thrive, severe muscle weakness, spasticity and psychomotor retardation. Vision and hearing are impaired.

Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release. In pancreatic cells, it forms KATP channels with KCNJ11; KCNJ11 forms the channel pore while ABCC8 is required for activation and regulation

Cell membrane

Leucine-induced hypoglycemia

Rare cause of hypoglycemia and is described as a condition in which symptomatic hypoglycemia is provoked by high protein feedings. Hypoglycemia is also elicited by administration of oral or intravenous infusions of a single amino acid, leucine.

Lysosomal enzyme involved in the degradation pathway of dermatan sulfate and heparan sulfate

Lysosome

Mucopolysaccharidosis 2

An X-linked lysosomal storage disease characterized by intracellular accumulation of heparan sulfate and dermatan sulfate and their excretion in urine. Most children with MPS2 have a severe form with early somatic abnormalities including skeletal deformities, hepatosplenomegaly, and progressive cardiopulmonary deterioration. A prominent feature is neurological damage that presents as developmental delay and hyperactivity but progresses to intellectual disability and dementia. They die before 15 years of age, usually as a result of obstructive airway disease or cardiac failure. In contrast, those with a mild form of MPS2 may survive into adulthood, with attenuated somatic complications and often without intellectual disability.

Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes. This specific binding is essential for a functional PDH complex

Mitochondrion matrix

Pyruvate dehydrogenase E3-binding protein deficiency

A metabolic disorder characterized by decreased activity of the pyruvate dehydrogenase complex without observable reduction in the activities of enzymes E1, E2, or E3. Clinical features include hypotonia and psychomotor retardation.

Has a role in alternative splicing and transcription regulation (PubMed:29522154). Involved in both constitutive and alternative pre-mRNA splicing. May have a role in the recognition of the 3' splice site during the second step of splicing

NucleusNucleus speckleCytoplasm

Intellectual developmental disorder, autosomal recessive 70

A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT70 patients manifest impaired intellectual development, mild facial dysmorphism, febrile seizures, and behavioral abnormalities.

Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10) (PubMed:10231530, PubMed:11489939, PubMed:16725361). Plays a role in the control of insulin secretion by inhibiting the activation of glutamate dehydrogenase 1 (GLUD1), an enzyme that has an important role in regulating amino acid-induced insulin secretion (By similarity). Plays a role in the maintenance of normal spermatogenesi

Mitochondrion matrix

3-alpha-hydroxyacyl-CoA dehydrogenase deficiency

An autosomal recessive, metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death.

Triosephosphate isomerase is an extremely efficient metabolic enzyme that catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde-3-phosphate (G3P) in glycolysis and gluconeogenesis It is also responsible for the non-negligible production of methylglyoxal a reactive cytotoxic side-product that modifies and can alter proteins, DNA and lipids

Cytoplasm

Triosephosphate isomerase deficiency

An autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy.

Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. Forms with the glucose-6-phosphate transporter (SLC37A4/G6PT) the complex responsible for glucose production in the terminal step of glycogenolysis and gluconeogenesis. Hence, it is the key enzyme in homeostatic regulation of blood glucose levels

Endoplasmic reticulum membrane

Glycogen storage disease 1A

A metabolic disorder characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Patients manifest a wide range of clinical symptoms and biochemical abnormalities, including hypoglycemia, severe hepatomegaly due to excessive accumulation of glycogen, kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia.

Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also locali

Mitochondrion matrixNucleusCell projection, cilium, flagellumCytoplasmic vesicle, secretory vesicle, acrosome

Dihydrolipoamide dehydrogenase deficiency

An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism.

Together with PDHB forms the heterotetrameric E1 subunit of the pyruvate dehydrogenase (PDH) complex (PubMed:17474719, PubMed:19081061). The PDH complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links cytoplasmic glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle (PubMed:19081061, PubMed:7782287). It contains multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide

Mitochondrion matrix

Pyruvate dehydrogenase E1-alpha deficiency

An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.

Non-catalytic component of the RNA exosome complex which has 3'->5' exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding 'pervasive' transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defe

CytoplasmNucleus, nucleolusNucleus

Pontocerebellar hypoplasia 1B

A severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement.

E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates (PubMed:12629548, PubMed:17449468, PubMed:18711448). Functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are necessary for IREB2 ubiquitination (PubMed:12629548). Promotes ubiquitination of TAB2 and IRF3 and their degradation by the proteasome (PubMed:17449468, PubMed:18711448). Component of the LUBAC complex which conjug

Polyglucosan body myopathy 1 with or without immunodeficiency

A disease characterized by polyglucosan storage myopathy associated with early-onset progressive muscle weakness and progressive dilated cardiomyopathy, which may necessitate cardiac transplant in severe cases. Some patients present with severe immunodeficiency, invasive bacterial infections and chronic autoinflammation.

Lysosome

Mucopolysaccharidosis 1H

A severe form of mucopolysaccharidosis type 1, a rare lysosomal storage disease characterized by progressive physical deterioration with urinary excretion of dermatan sulfate and heparan sulfate. Patients with MPS1H usually present, within the first year of life, a combination of hepatosplenomegaly, skeletal deformities, corneal clouding and severe intellectual disability. Obstructive airways disease, respiratory infection and cardiac complications usually result in death before 10 years of age.

Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling (By similarity). B-cell receptor (BCR) signaling requires a tight regulation of several protein tyrosine kinases and phosphatases, and associated coreceptors (By similarity). Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation (By similarity). Signaling through BLK plays an important role in transmitting signals through surface immunog

Cell membrane

Maturity-onset diabetes of the young 11

A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.

Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver

Secreted

Hyperproinsulinemia

An autosomal dominant condition characterized by elevated levels of serum proinsulin-like material.

CytoplasmCytoplasm, cytoskeleton

Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. I

Endoplasmic reticulum membrane

Intellectual developmental disorder, autosomal recessive 7

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization (PubMed:21730168, PubMed:22330775). Acts as an actin nucleation factor and promotes assembly of actin filaments together with SPIRE1 and SPIRE2 (PubMed:21730168, PubMed:22330775). Involved in intracellular vesicle transport along actin fibers, providing a novel link between actin cytoskeleton dynamics and intracellular transport (By similarity). Required for asymmetric spindle positioning, asymmetric oocyte

Cytoplasm, cytoskeletonCytoplasm, cytosolCytoplasm, perinuclear regionNucleusNucleus, nucleolusCell membraneCytoplasmic vesicle membraneCytoplasm, cell cortex

Intellectual developmental disorder, autosomal recessive 47

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT47 patients show delayed development, with cognition and speech more affected than motor skills.

Histone methyltransferase that dimethylates histone H3 at 'Arg-17', forming asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling (By similarity). Maternal factor involved in epigenetic chromatin reprogramming of the paternal genome in the zygote: mediates H3R17me2a, promoting histone H3.3 incorporation in the male pronucleus, leading to TET3 recruitment and subsequent DNA demethylation (By similarity)

NucleusCytoplasm

Intellectual developmental disorder, autosomal recessive 44

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT44 manifestations include mild to severe cognitive impairment, delayed psychomotor development, seizures in some patients, and dysmorphic features.

Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting

Early endosome

Intellectual developmental disorder, autosomal recessive 43

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis (PubMed:15073321, PubMed:16652156, PubMed:17159900, PubMed:17289572, PubMed:9044836). Also recruits CASP2 to the TNFR-1 signaling complex through its interaction with RIPK1 and TRADD and may play a role in the tumor necrosis factor-mediated signaling pathway (PubMed:8985253)

CytoplasmNucleus

Intellectual developmental disorder, autosomal recessive 34, with variant lissencephaly

A disorder characterized by mild to moderate intellectual disability, megalencephaly or enlarged head circumference, and a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures.

Mutarotase that catalyzes the interconversion of beta-D-galactose and alpha-D-galactose during galactose metabolism (PubMed:12753898). Beta-D-galactose is metabolized in the liver into glucose 1-phosphate, the primary metabolic fuel, by the action of four enzymes that constitute the Leloir pathway: GALM, GALK1 (galactokinase), GALT (galactose-1-phosphate uridylyltransferase) and GALE (UDP-galactose-4'-epimerase) (PubMed:30451973). Involved in the maintenance of the equilibrium between the beta-

Cytoplasm

Galactosemia 4

A form of galactosemia, an inborn error of galactose metabolism typically manifesting in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis and cataract. GALAC4 inheritance is autosomal recessive.

Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake (PubMed:10227690, PubMed:10954735, PubMed:18245775, PubMed:19449892, PubMed:25982116, PubMed:27078104, PubMed:32860739). Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses (PubMed:18245775, PubMed:19449892). Most important energy carrier of the brain: present at the blood-brain barrier and assures the energy-independent, facilitative trans

Cell membraneMelanosomePhotoreceptor inner segment

GLUT1 deficiency syndrome 1

A neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe intellectual disability.

Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+)

CytoplasmMitochondrion inner membrane

Lactate dehydrogenase B deficiency

A condition with no deleterious effects on health. LDHBD is of interest to laboratory medicine mainly because it can cause misdiagnosis in those disorders in which elevation of serum LDH is expected.

Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1 (PubMed:20980548, PubMed:28592437, PubMed:34880493, PubMed:37217492, PubMed:38057552). Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:28592437, PubMed:34880493). Unlike SLC5A1/SGLT1, requires the auxiliary protein PDZK1IP1/MAP17 for full transporter activity (PubMed:3

Apical cell membrane

Renal glucosuria

A disorder characterized by persistent isolated glucosuria, normal fasting serum glucose concentration, decreased renal tubular resorption of glucose from the urine, and absence of any other signs of tubular dysfunction.

Essential for the degradation of glycogen in lysosomes (PubMed:14695532, PubMed:18429042, PubMed:1856189, PubMed:7717400). Has highest activity on alpha-1,4-linked glycosidic linkages, but can also hydrolyze alpha-1,6-linked glucans (PubMed:29061980)

LysosomeLysosome membrane

Pompe disease, infantile-onset

An early-onset form of Pompe disease, an autosomal recessive lysosomal storage disease characterized by lysosomal alpha-glucosidase deficiency, a broad clinical spectrum and age at onset ranging from infancy to adulthood. The classic early-onset form of IOPD presents at birth with massive accumulation of glycogen in muscle, heart and liver. Cardiomyopathy and muscular hypotonia are the cardinal features of this form whose life expectancy is less than two years. A milder infantile form manifests as progressive muscular disorder of childhood and patients have better prognosis.

E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for pro

Endoplasmic reticulumNucleus

Myoclonic epilepsy of Lafora 2

A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. MELF2 is an autosomal recessive, severe form characterized by onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, myoclonic jerks, generalized seizures, and often visual hallucination. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. At the cellular level, MELF2 is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle.

Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation (PubMed:19306108). Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium (PubMed:19306108). In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels (By similarity)

LysosomeCell surface

Mucopolysaccharidosis 6

A form of mucopolysaccharidosis, a group of lysosomal storage diseases characterized by defective degradation of glycosaminoglycans, resulting in their excessive accumulation and secretion. The diseases are progressive and often display a wide spectrum of clinical severity. MPS6 is an autosomal recessive form characterized by intracellular accumulation of dermatan sulfate. Clinical features can include abnormal growth, short stature, stiff joints, skeletal malformations, corneal clouding, hepatosplenomegaly, and cardiac abnormalities.

Catalyzes the hydrolysis of a wide range of substrates including cholesteryl esters, phospholipids, lysophospholipids, di- and tri-acylglycerols, and fatty acid esters of hydroxy fatty acids (FAHFAs) (PubMed:10220579, PubMed:27509211, PubMed:27650499, PubMed:8471055). Preferentially hydrolyzes FAHFAs with the ester bond further away from the carboxylate. Unsaturated FAHFAs are hydrolyzed more quickly than saturated FAHFAs (By similarity). Has an essential role in the complete digestion of dietar

Secreted

Maturity-onset diabetes of the young 8 with exocrine dysfunction

An autosomal dominant form of diabetes characterized by a primary defect in insulin secretion, exocrine pancreatic dysfunction, altered pancreatic morphology, recurrent abdominal pain, and fecal elastase deficiency. Disease onset is at less than 25 years of age.

Transcription factor (PubMed:10207080, PubMed:9748269). Activates the epsilon- and gamma-globin gene promoters and, to a much lower degree, the beta-globin gene and represses promoters containing SP1-like binding inhibiting cell growth (PubMed:10207080, PubMed:16131492, PubMed:9748269). Represses transcription of SMAD7 which enhances TGF-beta signaling (By similarity). Induces apoptosis (By similarity)

Nucleus

Maturity-onset diabetes of the young 7

A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.

Plays an important role in the differentiation and development of pancreatic islet beta cells. Transcriptional repressor that binds to a common element in the glucagon, insulin and somatostatin promoters. Competes with PAX6 for this same promoter binding site. Isoform 2 appears to be a dominant negative form antagonizing PAX4 transcriptional activity

Nucleus

Type 2 diabetes mellitus

A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.

Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698)

Nucleus

Maturity-onset diabetes of the young 1

A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.

Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis (PubMed:29263200). Regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotropin-releasing hormone production (PubMed:29263200). WDR11 complex facilitates the tethering of Adaptor protein-1 complex (AP-1)-derived vesicles. WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture

Cytoplasm, cytoskeleton, cilium basal bodyCytoplasmNucleusCytoplasm, cytoskeleton, cilium axonemeCytoplasmic vesicleGolgi apparatus, trans-Golgi network

Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. T

Cytoplasm

Intellectual developmental disorder, autosomal recessive 67

A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Some MRT67 patients manifest seizures and sensorineural hearing loss.

Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:24952722, PubMed:27214403, PubMed:28262558). Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5 (PubMed:24952722). In contrast, may act as

Nucleus

Intellectual developmental disorder, autosomal recessive 65

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT65 patients have moderate to severe intellectual disability, developmental delay, and facial dysmorphism. Camptodactyly is present in some patients.

Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a s

Nucleus

Intellectual developmental disorder, autosomal recessive 18, with or without epilepsy

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

Intestinal trehalase is probably involved in the hydrolysis of ingested trehalose

Cell membrane

Trehalase deficiency

An autosomal recessive condition characterized by the inability to digest trehalose, a disaccharide found in mushrooms, products containing baker's yeast, and dried food. Individuals with trehalase deficiency suffer from abdominal pain, increased rectal flatulence, and diarrhea due to osmotic water flow into the colon.

Catalyzes the rate-limiting step of the non-oxidative phase in the pentose phosphate pathway. Catalyzes the reversible conversion of sedheptulose-7-phosphate and D-glyceraldehyde 3-phosphate into erythrose-4-phosphate and beta-D-fructose 6-phosphate (PubMed:18687684, PubMed:8955144). Not only acts as a pentose phosphate pathway enzyme, but also affects other metabolite pathways by altering its subcellular localization between the nucleus and the cytoplasm (By similarity)

NucleusCytoplasm

Transaldolase deficiency

An inborn error of the pentose phosphate pathway resulting in early-onset multisystem disease. Clinical features include growth retardation, dysmorphic features, cutis laxa, congenital heart disease, hepatosplenomegaly, telangiectases of the skin, pancytopenia, and bleeding tendency.

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

Ribose 5-phosphate isomerase deficiency

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

Nucleus

Phosphorylase b kinase catalyzes the phosphorylation of serine in certain substrates, including troponin I. The alpha chain may bind calmodulin

Cell membrane

Glycogen storage disease 9D

A metabolic disorder characterized by slowly progressive, predominantly distal muscle weakness and atrophy. Clinical features include exercise intolerance with early fatigability, pain, cramps and occasionally myoglobinuria.

Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase

Lysosome membrane

Mucopolysaccharidosis 3C

A form of mucopolysaccharidosis type 3, an autosomal recessive lysosomal storage disease due to impaired degradation of heparan sulfate. MPS3 is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life.

Plays an important role in the degradation of dermatan and keratan sulfates

Lysosome

Mucopolysaccharidosis 7

A form of mucopolysaccharidosis, a group of lysosomal storage diseases characterized by defective degradation of glycosaminoglycans, resulting in their excessive accumulation and secretion. The diseases are progressive and often display a wide spectrum of clinical severity. MPS7 is an autosomal recessive form with a highly variable phenotype, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment.

Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells (PubMed:29286281, PubMed:34815345). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is

Membrane

Hyperinsulinemic hypoglycemia, familial, 2

A form of hyperinsulinemic hypoglycemia, a clinically and genetically heterogeneous disorder characterized by inappropriate insulin secretion from the pancreatic beta-cells in the presence of low blood glucose levels. HHF2 is a common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF2 inheritance can be autosomal dominant or autosomal recessive.

Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. As part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Binds preferentiall

NucleusCytoplasm, cytosol

Pancreatic agenesis 1

A disease characterized by isolated hypoplasia or agenesis of the pancreas, pancreatic beta-cell failure resulting in neonatal insulin-dependent diabetes mellitus, and exocrine pancreatic insufficiency.

ATPase involved both in DNA repair and rescue of stalled ribosomes (PubMed:22055184, PubMed:28757607, PubMed:32099016, PubMed:32579943, PubMed:36302773). 3'-5' DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-stranded regions (PubMed:22055184). Also involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades

NucleusNucleus speckleCytoplasm, cytosol

Intellectual developmental disorder, autosomal recessive 81

An autosomal recessive disorder characterized by variable features including mild to severe developmental delay, hypotonia, feeding difficulties, extreme fatigue, and neurobehavioral abnormalities.

Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network

Cytoplasm, cytosolCell membrane

Intellectual developmental disorder, autosomal recessive 61

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT61 patients manifest delayed psychomotor development, moderate to severe intellectual disability, and variable dysmorphic facial features. Refractory seizures and brain abnormalities are present in severely affected patients.

Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid (PubMed:7536611, PubMed:8730589, PubMed:14511640). L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system (By similarity). Binding of the excitatory neurotransmitter L-glutamate induces a conformational change leading to the opening of the cation channel, converting the chemical signal to an electric

Cell membranePostsynaptic cell membrane

Intellectual developmental disorder, autosomal recessive 6

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT6 patients display mild to severe intellectual disability and psychomotor development delay in early childhood. Patients do not have neurologic problems, congenital malformations, or facial dysmorphism. Body height, weight, and head circumference are normal.

Phosphatase involved in the dephosphorylation of myo-inositol monophosphates to generate myo-inositol (PubMed:17068342, PubMed:8718889, PubMed:9462881). Is also able to dephosphorylate scyllo-inositol-phosphate, myo-inositol 1,4-diphosphate, scyllo-inositol-1,3-diphosphate and scyllo-inositol-1,4-diphosphate (PubMed:17068342). Also dephosphorylates in vitro other sugar-phosphates including D-galactose-1-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosph

Cytoplasm

Intellectual developmental disorder, autosomal recessive 59

A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.

Adenosine kinase that mediates the phosphorylation of the purine nucleoside adenosine at the 5' position in an ATP-dependent manner: catalyzes phosphorylation of both unmodified and modified adenosines (PubMed:21963049, PubMed:40840445, PubMed:6246102, PubMed:8577746, PubMed:9070863). Plays a key role in the detoxification of modified adenosines containing N(6)-methylated adenine (m6A) post-transcriptional modification (PubMed:40840445). Modified nucleosides are derived from the degradation of R

Cytoplasm, cytosolNucleusCytoplasm

Hypermethioninemia due to adenosine kinase deficiency

A metabolic disorder characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine and S-adenosylhomocysteine. Homocysteine levels are typically normal.

Mitochondrial carbonic anhydrase that catalyzes the reversible conversion of carbon dioxide to bicarbonate/HCO3 (PubMed:24530203, PubMed:8356065). Mitochondria are impermeable to HCO3, and thus this intramitochondrial carbonic anhydrase is pivotal in providing HCO3 for multiple mitochondrial enzymes that catalyze the formation of essential metabolites of intermediary metabolism in the urea and Krebs cycles (PubMed:24530203)

Mitochondrion

Hyperammonemia due to carbonic anhydrase VA deficiency

An autosomal recessive inborn error of metabolism, clinically characterized by infantile hyperammonemic encephalopathy. Metabolic abnormalities include hypoglycemia, hyperlactatemia, metabolic acidosis and respiratory alkalosis.