LCN2

Homo sapiens (Human)

p25; Siderocalin LCN2; Oncogene 24p3; NGAL; Lipocalin-2; LCN2; 25 kDa alpha-2-microglobulin-related subunit of MMP-9

Calycin superfamily, Lipocalin family

Calycin family

Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,5-dihydroxybenzoic acid (2,5- DHBA), a siderophore that shares structural similarities withbacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity, possibly by sequestrating iron, leading to limit bacterial growth. .

Pseudovaginal perineoscrotal hypospadias (PPSH) [MIM:264600]: A form of male pseudohermaphroditism in which 46,XY males show ambiguous genitalia at birth, including perineal hypospadias and a blind perineal pouch, and develop masculinization at puberty. The name of the disorder stems from the finding of a blind-ending perineal opening resembling a vagina and a severely hypospadiac penis with the urethra opening onto the perineum. {ECO:0000269|PubMed:10718838, ECO:0000269|PubMed:10898110, ECO:0000269|PubMed:10999800, ECO:0000269|PubMed:12843198, ECO:0000269|PubMed:15064320, ECO:0000269|PubMed:1522235, ECO:0000269|PubMed:15528927, ECO:0000269|PubMed:15770495, ECO:0000269|PubMed:16098368, ECO:0000269|PubMed:16181229, ECO:0000269|PubMed:7554313, ECO:0000269|PubMed:8626825, ECO:0000269|PubMed:8768837, ECO:0000269|PubMed:9208814, ECO:0000269|PubMed:9745434, ECO:0000269|PubMed:9843052}. The disease is caused by variants affecting the gene represented in this entry.

DB02710; DB01672; DB01926; DB04043; DB01631; DB04476

P49419-2; Q9NXW9; Q8WXI3; Q12797-6; Q9BXY8; Q96LC9; P49069; P24863; Q9UKJ5; Q9H1P6; Q9H6B4; O14595; Q08426; Q6NZ36-4; B3EWG5; Q7Z4H3; Q6ISS4; Q5TA76; P80188; Q9UIQ6-2; Q9Y6Y9; Q96JG8; Q8IXL7-2; Q969H8; Q969S2; Q17RF5; P07237; P13667; Q96FA3; Q9NRD5; Q13526; Q9UGP5-2; Q12837; P54646; Q86Y79; O60895; Q9BWG6; P60059; O43765; Q96EQ0; Q8IYX1; Q9UL33-2; P20396; O43715; Q13049; Q99816; Q5W5X9-3; Q99757; P57075-2; Q969M7; Q9UMX0; Q9UHD9; P15692-12; Q14119; Q9Y6T4; Q9H0D6; O96006; A0A1U9X8X8

NA

3D-structure; Alternative splicing; Apoptosis; Cytoplasmic vesicle; Direct protein sequencing; Disulfide bond; Glycoprotein; Immunity; Innate immunity; Ion transport; Iron; Iron transport; Proteomics identification; Pyrrolidone carboxylic acid; Reference proteome; Secreted; Signal; Transport

A

19748.4

172

0.13

30.73

7.71

0.72

-10.29

F2R

Homo sapiens (Human)

NA

TR;PAR1;CF2R

G-protein coupled receptor 1 family

Signaling protein / antagonist

G-protein alpha-subunit binding.G-protein beta-subunit binding.G-protein coupled receptor activity.Receptor binding.Thrombin-activated receptor activity.

3-ketothiolase deficiency (3KTD) [MIM:203750]: An autosomal recessive inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype. {ECO:0000269|PubMed:1346617, ECO:0000269|PubMed:1715688, ECO:0000269|PubMed:7728148, ECO:0000269|PubMed:9744475}. The disease is caused by variants affecting the gene represented in this entry.

DB05361; DB00086; DB11300; DB09030

Q03135; Q9UNN8

NA

3D-structure; Blood coagulation; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Hemostasis; Membrane; Phosphoprotein; Proteomics identification; Receptor; Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix

A

31193.7

282

0.16

36.7

8.2

2.98

-10.26

XDH

Homo sapiens (Human)

Xanthine oxidase; Xanthine dehydrogenase; XDHA

Xanthine dehydrogenase family

CH/CH(2) oxidoreductase

Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro). Key enzyme in purine degradation.

Xanthinuria 1 (XAN1) [MIM:278300]: A disorder characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. XAN1 is due to isolated xanthine dehydrogenase deficiency. Patients can metabolize allopurinol. {ECO:0000269|PubMed:10844591, ECO:0000269|PubMed:11379872, ECO:0000269|PubMed:14551354, ECO:0000269|PubMed:9153281}. The disease is caused by variants affecting the gene represented in this entry.

DB00640; DB00041; DB00437; DB00993; DB00958; DB01136; DB00856; DB00515; DB00746; DB03328; DB00997; DB03516; DB12466; DB04854; DB03147; DB04335; DB01020; DB00583; DB00170; DB01033; DB00157; DB03841; DB00336; DB01250; DB05262; DB06478; DB01168; DB00339; DB00127; DB01685; DB00831

Q9Y3R0-3

NA

2Fe-2S; 3D-structure; Cytoplasm; Disease variant; Disulfide bond; FAD; Flavoprotein; Iron; Iron-sulfur; Metal-binding; Molybdenum; NAD; Oxidoreductase; Peroxisome; Proteomics identification; Reference proteome; Secreted

A,B,C,D

143697

1307

0.08

37.9

8.01

7.07

-10.27

LCMT1

Homo sapiens (Human)

NA

CGI-68;LCMT

Methyltransferase superfamily, LCMT family

Transferase

Protein C-terminal carboxyl O-methyltransferase activity.Protein C-terminal leucine carboxyl O-methyltransferase activity.S-adenosylmethionine-dependent methyltransferase activity.

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS) [MIM:617710]: An autosomal recessive, mitochondrial disorder with a broad phenotypic spectrum ranging from severe neonatal lactic acidosis, encephalomyopathy and early death to an attenuated course with milder manifestations. Clinical features include delayed psychomotor development, intellectual disability, hypotonia, dystonia, ataxia, and spasticity. Severe combined respiratory chain deficiency may be found in severely affected individuals. {ECO:0000269|PubMed:28236339, ECO:0000269|PubMed:28650581, ECO:0000269|PubMed:28905505, ECO:0000269|PubMed:30920170, ECO:0000269|PubMed:35074316}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Parkinsonism-dystonia 3, childhood-onset (PKDYS3) [MIM:619738]: An autosomal recessive neurodegenerative disorder with onset in infancy or early childhood. Affected individuals present with progressive movement abnormalities, including parkinsonism with tremor, dystonia, myoclonus ataxia, and hyperkinetic movements such as ballismus. The parkinsonism features may be responsive to treatment with levodopa, although many patients develop levodopa-induced dyskinesia. Some patients may have mild cognitive impairment or psychiatric disturbances. {ECO:0000269|PubMed:29120065, ECO:0000269|PubMed:31970218, ECO:0000269|PubMed:34890876}. The disease is caused by variants affecting the gene represented in this entry.

DB00149

P51116

2.1.1.233

3D-structure; Alternative splicing; Methyltransferase; Proteomics identification; Reference proteome; S-adenosyl-L-methionine; Transferase

A,B,C,D,E,F,G,H

35803

310

0.08

42.77

6.13

-3.58

-10.27

HRV P3C

Human rhinovirus 2 (HRV-2)

Rhinovirus P3C

Picornaviruses polyprotein family

NA

Capsid protein VP1: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is 300 Angstroms in diameter, composed of 60 copies of each capsid protein and enclosing the viral positive strand RNA genome. Capsid protein VP1 mainly forms the vertices of the capsid. Capsid protein VP1 interacts with host VLDLR to provide virion attachment to target host cells. This attachment induces virion internalization. Tyrosine kinases are probably involved in the entry process. After binding to its receptor, the capsid undergoes conformational changes. Capsid protein VP1 N-terminus (that contains an amphipathic alpha-helix) and capsid protein VP4 are externalized. Together, they shape a pore in the host membrane through which viral genome is translocated to host cell cytoplasm. After genome has been released, the channel shrinks (By similarity).

Charcot-Marie-Tooth disease, axonal, 2DD (CMT2DD) [MIM:618036]: A dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:29499166}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Hypomagnesemia, seizures, and impaired intellectual development 2 (HOMGSMR2) [MIM:618314]: An autosomal dominant disease characterized by generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persist despite magnesium supplementation and are associated with significant intellectual disability. {ECO:0000269|PubMed:30388404}. The disease is caused by variants affecting the gene represented in this entry.

DB02313; DB03017

NA

EC 3.4.22.28

3D-structure; Activation of host autophagy by virus; ATP-binding; Autocatalytic cleavage; Capsid protein; Covalent protein-RNA linkage; DNA replication; Eukaryotic host gene expression shutoff by virus; Eukaryotic host translation shutoff by virus; Helicase; Host cytoplasm; Host cytoplasmic vesicle; Host gene expression shutoff by virus; Host membrane; Host mRNA suppression by virus; Host nucleus; Host-virus interaction; Hydrolase; Inhibition of host innate immune response by virus; Inhibition of host mRNA nuclear export by virus; Inhibition of host RIG-I by virus; Inhibition of host RLR pathway by virus; Ion channel; Ion transport; Lipoprotein; Magnesium; Membrane; Metal-binding; Myristate; Nucleotide-binding; Nucleotidyltransferase; Phosphoprotein; Pore-mediated penetration of viral genome into host cell; Protease; Repeat; RNA-binding; RNA-directed RNA polymerase; T=pseudo3 icosahedral capsid protein; Thiol protease; Transferase; Transport; Viral attachment to host cell; Viral immunoevasion; Viral ion channel; Viral penetration into host cytoplasm; Viral RNA replication; Virion; Virus endocytosis by host; Virus entry into host cell; Zinc; Zinc-finger

1

30610.1

269

0.1

55.66

6.86

-0.38

-10.27

CASP7

Homo sapiens (Human)

MCH3; ICE-like apoptotic protease 3; ICE-LAP3; CMH-1; CASP-7; Apoptotic protease Mch-3

Peptidase C14A family

Peptidase

Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Overexpression promotes programmed cell death. Involved in the activation cascade of caspases responsible for apoptosis execution.

Pregnancy loss, recurrent, 3 (RPRGL3) [MIM:614391]: A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. {ECO:0000269|PubMed:17339269}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

DB05408; DB03384; DB06255

Q13490; P83105; P42858; Q8N4N3-2; P43364; Q16236; Q9GZT8; Q13177; P27986-2; P21673; Q86WV1-2; P17405; P98170

EC 3.4.22.60

3D-structure; Acetylation; Allosteric enzyme; Alternative splicing; Apoptosis; Cytoplasm; Hydrolase; Nucleus; Phosphoprotein; Protease; Proteomics identification; Reference proteome; RNA-binding; Secreted; Thiol protease; Ubl conjugation; Zymogen

A,B

47441.5

417

0.11

20.98

8.38

6.12

-10.27

MTNR1A

Homo sapiens (Human)

Mel1a receptor; Mel1AR; Mel-1A-R

G-protein coupled receptor 1 family

GPCR rhodopsin

Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. High affinity receptor for melatonin.

Spermatogenic failure 5 (SPGF5) [MIM:243060]: An infertility disorder caused by spermatogenesis defects. Semen from affected men show close to 100% morphologically abnormal multiflagellar spermatozoa with low motility, oversized irregular heads, and abnormal midpiece and acrosome. {ECO:0000269|PubMed:17435757, ECO:0000269|PubMed:21733974}. The disease is caused by variants affecting the gene represented in this entry.

DB06594; DB01065; DB00980; DB02709; DB09071

P27797; A8MQ03; Q8IUG1; P49286; O76081; P57088

NA

3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; Receptor; Reference proteome; Transducer; Transmembrane; Transmembrane helix

D

31301

276

0.15

37.33

9.22

9.92

-10.26

benC

Acinetobacter baylyi (strain ATCC 33305 / BD413 / ADP1)

NA

ACIAD1438

Bacterial ring-hydroxylating dioxygenase ferredoxin reductase family

Oxidoreductase

2 iron, 2 sulfur cluster binding.Electron carrier activity.Ferredoxin-NAD+ reductase activity.Metal ion binding.

Adenine phosphoribosyltransferase deficiency (APRTD) [MIM:614723]: An enzymatic deficiency that can lead to urolithiasis and renal failure. Patients have 2,8-dihydroxyadenine (DHA) urinary stones. {ECO:0000269|PubMed:11243733, ECO:0000269|PubMed:1353080, ECO:0000269|PubMed:15571218, ECO:0000269|PubMed:1746557, ECO:0000269|PubMed:21635362, ECO:0000269|PubMed:3343350, ECO:0000269|PubMed:3680503, ECO:0000269|PubMed:7915931}. The disease is caused by variants affecting the gene represented in this entry.

DB03147

NA

1.18.1.3

2Fe-2S; 3D-structure; Aromatic hydrocarbons catabolism; FAD; Flavoprotein; Iron; Iron-sulfur; Metal-binding; NAD; Oxidoreductase

A,B

37496.7

337

0.1

47.02

4.75

-18.87

-10.26

EBP

Homo sapiens (Human)

Emopamilbinding protein; EBP; Delta(8)Delta(7) sterol isomerase; D8D7 sterol isomerase; 3betahydroxysteroidDelta(8),Delta(7)isomerase

EBP family

Intramolecular oxidoreductases

Catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers.

Chondrodysplasia punctata 2, X-linked dominant (CDPX2) [MIM:302960]: A clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. The key clinical features of CDPX2 are chondrodysplasia punctata, linear ichthyosis, cataracts and short stature. CDPX2 is a rare disorder of defective cholesterol biosynthesis, biochemically characterized by an increased amount of 8-dehydrocholesterol and cholest-8(9)-en-3-beta-ol in the plasma and tissues. {ECO:0000269|PubMed:10391218, ECO:0000269|PubMed:10391219, ECO:0000269|PubMed:10942423, ECO:0000269|PubMed:11493318, ECO:0000269|PubMed:18176751, ECO:0000269|PubMed:25814754}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: MEND syndrome (MEND) [MIM:300960]: An X-linked recessive disorder associated with a defect in sterol biosynthesis. Disease manifestations and severity are highly variable. Clinical features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. {ECO:0000269|PubMed:12503101, ECO:0000269|PubMed:20949533, ECO:0000269|PubMed:24459067, ECO:0000269|PubMed:24700572}. The disease is caused by variants affecting the gene represented in this entry.

DB00675

O95870; Q86W74-2; Q13520; Q3SXY8; Q8N6S5; Q9H2C2; Q9HD20-3; O95393; Q12983; Q8WVV5; P06681; O14523; Q8WVX3-2; P01031; Q6UWT4; Q9P0B6; Q8NHW4; P25942; Q07108; P60033; O14735; P23141-3; Q9H9P2; Q8NHS1; O43889-2; Q96BA8; P49447; O43169; P78329; P81534; Q9H1M4; Q96LL9; Q15125; Q08426; Q9BV81; P54849; Q9UKR5; Q9Y282; Q7L5A8; Q5JX71; Q96IV6; Q9UGM5; Q9Y3D6; Q14318; Q9BWH2; Q14802-3; Q9H0Q3; Q8WWP7; Q96F15; P29033; O95452; O14653; Q8TDT2; P02724; P30519; Q7Z5P4; Q9Y5U9; Q9Y5U4; Q8N5M9; Q5T700; Q68G75; Q7L5N7; Q7Z4F1; Q96AG4; Q16873; Q6ZSS7; P50281; Q5J8X5; Q9UHE5; O95167; Q9NX14; Q99519; Q92982; Q9NZG7; Q16617; Q8IXM6; Q2M2E3; Q9P0S3; Q53FV1; Q8N138; Q7RTS5; Q9Y342; Q04941; Q8IY26; Q01453; P54315; P43378; P15151; Q8N8N0; Q5QGT7; Q96GQ5; Q9NTJ5; Q969E2; O75396; Q9Y6X1; Q8N6R1; Q9BWM7; Q8TD22; Q8IWU4; Q96G79; Q2M3R5; Q9NVC3; P08195-4; Q96JW4; Q6P1K1; Q0VAQ4; Q9NRQ5; B2RUZ4; Q9BZL3; Q6UX34; Q86Y82; P61266; Q13190; O43752; O15400; Q9UNK0; O43759-2; P57105; Q8N2H4; Q96BZ9; P07204; O14925; Q96CP7; Q96MV1; P55061; Q9NV29; P17152; Q9BXJ8; A0PK00; Q9NV12; Q9BVK8; Q9NUH8; Q9P0S9; Q9NRX6; Q8N511; Q969S6; Q9BTX3; A2RU14; Q9H0R3; Q8NBD8; Q8WW34-2; Q9NWH2; Q9BU79; Q8TBM7; Q69YG0; Q9NW97; Q9H2L4; Q6PI78; Q8N2M4; Q8N661; Q5BJF2; Q9NSU2-1; A0AVG3; Q5TGU0; A5PKU2; Q9Y385; Q9Y5Z9; Q53HI1; Q9H1C4; Q9NZ43; P23763-3; P63027; Q15836; O75379; Q9P0L0; O95292; O95070; Q9Y548; Q9BSR8; Q96EC8; Q6UX98; O95159

EC 5.3.3.5

3D-structure; Acetylation; Cataract; Cholesterol biosynthesis; Cholesterol metabolism; Cytoplasmic vesicle; Disease variant; Dwarfism; Endoplasmic reticulum; Ichthyosis; Isomerase; Lipid biosynthesis; Lipid metabolism; Membrane; Nucleus; Proteomics identification; Reference proteome; Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix

A

24012.7

206

0.17

42.52

6.19

-3.19

-10.24

PRKAR1A

Homo sapiens (Human)

cAMP-dependent protein kinase type I-alpha regulatory subunit; Tissue-specific extinguisher 1; TSE1; PRKAR1; PKR1

CAMP-dependent kinase regulatory chain family

Kinase

Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

Carney complex 1 (CNC1) [MIM:160980]: CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. {ECO:0000269|PubMed:15371594, ECO:0000269|PubMed:18241045, ECO:0000269|PubMed:22785148, ECO:0000269|PubMed:23323113, ECO:0000269|PubMed:26405036}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Intracardiac myxoma (INTMYX) [MIM:255960]: Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Primary pigmented nodular adrenocortical disease 1 (PPNAD1) [MIM:610489]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. PPNAD1 is most often diagnosed in patients with Carney complex, a multiple neoplasia syndrome. However it can also be observed in patients without other manifestations. {ECO:0000269|PubMed:12213893}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Acrodysostosis 1, with or without hormone resistance (ACRDYS1) [MIM:101800]: A form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. However, not all patients show endocrine abnormalities. {ECO:0000269|PubMed:21651393, ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:22723333, ECO:0000269|PubMed:23043190, ECO:0000269|PubMed:23425300, ECO:0000269|PubMed:26405036}. The disease is caused by variants affecting the gene represented in this entry.

DB01790; DB02527; DB02315; DB05798

Q9GZX7; P24588; O43687-2; Q9BSF0; Q9H6J7-2; Q86Y01; P0C7A2-2; Q9H0R8; Q9H8W4; P17612; P31321; P51817; P35250; Q86UC2; Q01105; Q8N0X7; O96006; P03259-2

NA

3D-structure; Acetylation; Alternative splicing; cAMP; cAMP-binding; Cell membrane; Cushing syndrome; Direct protein sequencing; Disease variant; Disulfide bond; Membrane; Nucleotide-binding; Phosphoprotein; Proteomics identification; Reference proteome; Repeat

A

17007.4

149

0.08

49.36

6.36

-0.52

-10.24

TRBC1

Homo sapiens (Human)

TCRBC1; BV05S1J2.2

NA

NA

Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens. Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation. The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity. Constant region of T cell receptor (TR) alpha chain.

Immunodeficiency 57 with autoinflammation (IMD57) [MIM:618108]: An autosomal recessive primary immunodeficiency characterized by lymphopenia and recurrent viral, bacterial, and fungal infections. Patients exhibit early-onset inflammatory bowel disease involving the upper and lower gastrointestinal tract, and develop progressive polyarthritis. {ECO:0000269|PubMed:30026316}. The disease is caused by variants affecting the gene represented in this entry. RIPK1-deficient immune cells from IMD57 patients have impaired proinflammatory signaling leading to dysregulated cytokine secretion and are prone to necroptosis. {ECO:0000269|PubMed:30026316}.; DISEASE: Autoinflammation with episodic fever and lymphadenopathy (AIEFL) [MIM:618852]: An autosomal dominant immunologic disorder characterized by early onset of recurrent episodes of unexplained fever, lymphadenopathy, hepatosplenomegaly, and increased levels of inflammatory cytokines and chemokines in patient serum. {ECO:0000269|PubMed:31827280, ECO:0000269|PubMed:31827281}. The disease is caused by variants affecting the gene represented in this entry.

DB02740

NA

NA

3D-structure; Adaptive immunity; Cell membrane; Disulfide bond; Glycoprotein; Immunity; Immunoglobulin domain; Membrane; Proteomics identification; Receptor; Reference proteome; T cell receptor; Transmembrane; Transmembrane helix

C,B,A

84668.2

736

0.13

39.96

5.8

-14.36

-10.22

NOS3

Homo sapiens (Human)

Nitric oxide synthase, endothelial; NOSIII; NOS,type III; NOS type III; Endothelial nitric oxide synthase; Endothelial NOS; ENOS; EC-NOS; Constitutive NOS; CNOS

NOS family

Paired donor oxygen oxidoreductase

NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets. Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.

Variation Asp-298 in NOS3 may be associated with susceptibility to coronary spasm. {ECO:0000269|PubMed:11740345, ECO:0000269|PubMed:9737779}.

DB07001; DB02048; DB02911; DB02335; DB01997; DB03332; DB04534; DB07244; DB03100; DB03918; DB02207; DB03065; DB00125; DB02994; DB01833; DB00155; DB00997; DB07388; DB03974; DB02077; DB01821; DB09237; DB01110; DB03144; DB03305; DB01686; DB04559; DB02044; DB08019; DB08018; DB02027; DB02979; DB00435; DB04223; DB06154; DB03910; DB02141; DB03963; DB03707; DB02234; DB04018; DB00360; DB02589

P60709; P63010-2; Q8N6T3-3; Q9Y575-3; Q96FT7-4; Q5SZD1; Q16543; Q9UNS2; Q8IUI8; P35222; Q05193; O15287; Q08379; Q71DI3; P69905; P61978; Q12891; Q9UKT9; Q9Y2M5; Q14525; Q6DKI2; P43364-2; Q8N6F8; O94851; A4FUJ8; Q8N594; Q8IVI9; Q6X4W1-6; O15381-5; Q9NV79; Q16549; Q5T2W1; O75925; Q96I34; Q6ZMI0-5; P57052; Q9GZR2; Q96D59; Q8N6K7-2; Q9GZS3; Q8IUW3; Q7Z699; Q7Z698; P50502; Q9BR01-2; Q9NVV9; Q86WT6-2; Q9H347; P58304; Q9NZC7-5; Q9UNY5; P14079

EC 1.14.13.39

3D-structure; Alternative splicing; Calcium; Calmodulin-binding; Cell membrane; Cytoplasm; Cytoskeleton; Direct protein sequencing; FAD; Flavoprotein; FMN; Golgi apparatus; Heme; Iron; Lipoprotein; Membrane; Metal-binding; Myristate; NADP; Oxidoreductase; Palmitate; Phosphoprotein; Proteomics identification; Reference proteome; Zinc

A,B

90790.1

803

0.11

50.67

6.03

-9.56

-10.21

DHRS4

Homo sapiens (Human)

NA

SDR25C2;UNQ851/PRO1800

Short-chain dehydrogenases/reductases (SDR) family

Oxidoreductase

3-keto sterol reductase activity.Alcohol dehydrogenase [NAD(P)+] activity.Carbonyl reductase (NADPH) activity.NADP-retinol dehydrogenase activity.Oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor.Receptor binding.

Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}. The disease is caused by variants affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.

DB00162

NA

1.1.1.184

3D-structure; Acetylation; Alternative splicing; NADP; Nucleus; Oxidoreductase; Peroxisome; Phosphoprotein; Proteomics identification; Reference proteome

A,B,C,D

27006.8

254

0.04

48.02

7.61

0.66

-10.22

MTNR1B

Homo sapiens (Human)

Mel1b receptor; Mel1b melatonin receptor; Mel-1B-R

G-protein coupled receptor 1 family

GPCR rhodopsin

Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. High affinity receptor for melatonin.

Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269|PubMed:14657428, ECO:0000269|PubMed:15928254, ECO:0000269|PubMed:25040157}. The disease is caused by variants affecting the gene represented in this entry.

DB06594; DB01065; DB00980; DB02709; DB09071; DB15133

P28335; P48039; O76081; Q14669

NA

3D-structure; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; Receptor; Reference proteome; Transducer; Transmembrane; Transmembrane helix

A

50184.9

448

0.11

37.2

5.72

-5.68

-10.22

SETD2

Homo sapiens (Human)

p231HBP; hSET2; SET2; SET domain-containing protein 2; Protein-lysine N-methyltransferase SETD2; KMT3A; KIAA1732; Huntingtin-interacting protein B; Huntingtin-interacting protein 1; Huntingtin yeast p

Class V-like SAM-binding methyltransferase superfamily, Histone-lysine methyltransferase family, SET2 subfamily

Methyltransferase

Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation. Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A. Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction. Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR). Acts as a tumor suppressor. H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A. H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase. Required during angiogenesis. Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3. In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1. Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling. Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription. Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate.

Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:20054297, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}. The disease may be caused by variants affecting the gene represented in this entry. Defects of SETD2 are associated with loss of DNA methylation at non-promoter regions (PubMed:23792563). SETD2 defects lead to aberrant and reduced nucleosome compaction and chromatin association of key replication proteins, such as MCM7 and DNA polymerase delta, leading to hinder replication fork progression and prevent loading of RAD51 homologous recombination repair factor at DNA breaks (PubMed:25728682). {ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}.; DISEASE: Luscan-Lumish syndrome (LLS) [MIM:616831]: An autosomal dominant syndrome with a variable phenotype. Clinical features include macrocephaly, distinctive facial appearance, postnatal overgrowth, various degrees of learning difficulties, autism spectrum disorder, and intellectual disability. {ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:24852293, ECO:0000269|PubMed:26084711, ECO:0000269|PubMed:27317772}. The disease may be caused by variants affecting the gene represented in this entry.; DISEASE: Leukemia, acute lymphoblastic (ALL) [MIM:613065]: A subtype of acute leukemia, a cancer of the white blood cells. ALL is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphnodes. {ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24662245}. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16314571, ECO:0000269|PubMed:24509477}. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Intellectual developmental disorder, autosomal dominant 70 (MRD70) [MIM:620157]: An autosomal dominant disorder characterized by mild global developmental delay, moderately impaired intellectual disability with speech difficulties, and behavioral abnormalities. {ECO:0000269|PubMed:32710489}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Rabin-Pappas syndrome (RAPAS) [MIM:620155]: An autosomal dominant neurodevelopmental disorder characterized by severely impaired global development, intellectual disability, microcephaly, facial dysmorphism, and variable congenital anomalies affecting the skeletal, genitourinary, cardiac, and other organ systems. {ECO:0000269|PubMed:32710489}. The disease is caused by variants affecting the gene represented in this entry.

NA

P42858; P84022

EC 2.1.1.43

3D-structure; Activator; Alternative splicing; Antiviral defense; Autism spectrum disorder; Chromatin regulator; Chromosome; Coiled coil; Developmental protein; Differentiation; Disease variant; DNA damage; DNA repair; Host-virus interaction; Immunity; Innate immunity; Intellectual disability; Isopeptide bond; Metal-binding; Methyltransferase; Nucleus; Phosphoprotein; Proteomics identification; Reference proteome; S-adenosyl-L-methionine; Transcription; Transcription regulation; Transferase; Tumor suppressor; Ubl conjugation; Zinc

A

27416.8

237

0.11

55.47

7.51

0.99

-10.22

PRMT5

Homo sapiens (Human)

Shk1 kinase-binding protein 1 homolog; SKB1Hs; SKB1 homolog; SKB1; Protein arginine N-methyltransferase 5; Jak-binding protein 1; JBP1; IBP72; Histone-arginine N-methyltransferase PRMT5; HRMT1L5; 72 k

Class I-like SAM-binding methyltransferase superfamily, Protein arginine N-methyltransferase family

Methyltransferase

Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles. Methylates SUPT5H and may regulate its transcriptional elongation properties. Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development. Methylates histone H3 'Arg-8', which may repress transcription. Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage. Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation. Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity. Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9. Methylates and regulates SRGAP2 which is involved in cell migration and differentiation. Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter. Methylates GM130/GOLGA2, regulating Golgi ribbon formation. Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner. Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression. Symmetrically methylates NCL. Methylates TP53; methylation might possibly affect TP53 target gene specificity. Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA.

Epilepsy, nocturnal frontal lobe, 3 (ENFL3) [MIM:605375]: An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. {ECO:0000269|PubMed:11062464, ECO:0000269|PubMed:11104662}. The disease is caused by variants affecting the gene represented in this entry.

NA

P01019; Q9NX04; Q8WUW1; Q08289; P78371; Q16543; Q8N8U2; P54105; P21964-2; Q9NQ92; Q16526; Q9Y6K1; Q01094; Q08426; P38919; Q14241; O15197-2; Q6ZV65; P01100; O95995; P62993; Q8TE85; Q9BX10; P62805; P31269; Q00613; Q63ZY3; P03952; Q8TBB1; P06858; Q86UQ8-1; Q96HA8; Q8WVJ2; P24928; O14744; Q86U06; Q9BRS2; O75044; Q96RU7; P31930; P40337-2; Q9BQA1; P63104; Q96E35; Q91XC0; P03418; Q6ZV65-2

EC 2.1.1.320

3D-structure; Acetylation; Alternative splicing; Biological rhythms; Chromatin regulator; Chromosome; Cytoplasm; Direct protein sequencing; Golgi apparatus; Methyltransferase; Nucleus; Proteomics identification; Reference proteome; Repressor; S-adenosyl-L-methionine; Transcription; Transcription regulation; Transferase

A

71188.3

621

0.11

44.6

5.95

-9.68

-10.21

RXRB

Homo sapiens (Human)

Retinoid X receptor beta; Nuclear receptor subfamily 2 group B member 2; NR2B2

Nuclear hormone receptor family, NR2 subfamily

Nuclear hormone receptor

Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE). Receptor for retinoic acid.

Noonan syndrome 13 (NS13) [MIM:619087]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. NS13 inheritance is autosomal dominant. There is considerable variability in severity. {ECO:0000269|PubMed:32721402}. The disease is caused by variants affecting the gene represented in this entry.

DB08175; DB00459; DB00210; DB00523; DB00307; DB01393; DB03756; DB00926; DB01941; DB07929; DB02746; DB00412; DB00799; DB07080; DB00755

Q00975; Q9HB07; F1D8P7; Q13133; Q13133-3; Q96RI1-1; P04150; Q9NRD5; P37231; P10276; P10276-2; P10826-2; P13631; Q6IQ16; Q13137; Q96B26; Q08379; Q6A162; Q9UJV3-2; Q13133-3; Q96RI1-1; O43586; P10276; P10826-2; Q8IUQ4-2; O75528; Q12800; Q9UBB9; Q05BL1; P14373; O94972; Q96S82

NA

3D-structure; Alternative splicing; Cytoplasm; DNA-binding; Metal-binding; Methylation; Nucleus; Proteomics identification; Receptor; Reference proteome; Transcription; Transcription regulation; Zinc; Zinc-finger

A,C

28845.8

251

0.08

54.86

6.74

-0.6

-10.21

XDH

Homo sapiens (Human)

Xanthine oxidase; Xanthine dehydrogenase; XDHA

Xanthine dehydrogenase family

CH/CH(2) oxidoreductase

Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro). Key enzyme in purine degradation.

Xanthinuria 1 (XAN1) [MIM:278300]: A disorder characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. XAN1 is due to isolated xanthine dehydrogenase deficiency. Patients can metabolize allopurinol. {ECO:0000269|PubMed:10844591, ECO:0000269|PubMed:11379872, ECO:0000269|PubMed:14551354, ECO:0000269|PubMed:9153281}. The disease is caused by variants affecting the gene represented in this entry.

DB00640; DB00041; DB00437; DB00993; DB00958; DB01136; DB00856; DB00515; DB00746; DB03328; DB00997; DB03516; DB12466; DB04854; DB03147; DB04335; DB01020; DB00583; DB00170; DB01033; DB00157; DB03841; DB00336; DB01250; DB05262; DB06478; DB01168; DB00339; DB00127; DB01685; DB00831

Q9Y3R0-3

NA

2Fe-2S; 3D-structure; Cytoplasm; Disease variant; Disulfide bond; FAD; Flavoprotein; Iron; Iron-sulfur; Metal-binding; Molybdenum; NAD; Oxidoreductase; Peroxisome; Proteomics identification; Reference proteome; Secreted

A,B,C,D

143697

1307

0.08

37.9

8.01

7.07

-10.2

cocE

Rhodococcus sp. (strain MB1 Bresler)

NA

NA

CocE/NonD hydrolase family

Hydrolase

Carboxylic ester hydrolase activity.Dipeptidyl-peptidase activity.

Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (THMD5) [MIM:614458]: An autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits. {ECO:0000269|PubMed:22152682}. The disease is caused by variants affecting the gene represented in this entry.

DB03793; DB01795

NA

3.1.1.84

3D-structure; Cytoplasm; Direct protein sequencing; Hydrolase; Serine esterase

A

62127.9

574

0.09

26.62

4.56

-33.24

-10.2

GLP1R

Homo sapiens (Human)

GLP-1R; GLP-1-R; GLP-1 receptor

G-protein coupled receptor 2 family

GPCR secretin

Ligand binding triggers activation of a signaling cascade that leads to the activation of adenylyl cyclase and increased intracellular cAMP levels. Plays a role in regulating insulin secretion in response to GLP-1. G-protein coupled receptor for glucagon-like peptide 1 (GLP-1).

Lynch syndrome 2 (LYNCH2) [MIM:609310]: A form of Lynch syndrome, an autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. Lynch syndrome is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, it is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical Lynch syndrome is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected Lynch syndrome' or 'incomplete Lynch syndrome' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269|PubMed:10323887, ECO:0000269|PubMed:10375096, ECO:0000269|PubMed:10386556, ECO:0000269|PubMed:10413423, ECO:0000269|PubMed:10480359, ECO:0000269|PubMed:10598809, ECO:0000269|PubMed:10627141, ECO:0000269|PubMed:10660333, ECO:0000269|PubMed:10671064, ECO:0000269|PubMed:10713887, ECO:0000269|PubMed:10777691, ECO:0000269|PubMed:10882759, ECO:0000269|PubMed:11139242, ECO:0000269|PubMed:11427529, ECO:0000269|PubMed:11726306, ECO:0000269|PubMed:11748856, ECO:0000269|PubMed:11754112, ECO:0000269|PubMed:11781295, ECO:0000269|PubMed:11793442, ECO:0000269|PubMed:11839723, ECO:0000269|PubMed:11870161, ECO:0000269|PubMed:12095971, ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12200596, ECO:0000269|PubMed:12362047, ECO:0000269|PubMed:12373605, ECO:0000269|PubMed:12655562, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14635101, ECO:0000269|PubMed:14961575, ECO:0000269|PubMed:15064764, ECO:0000269|PubMed:15139004, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:15365996, ECO:0000269|PubMed:16083711, ECO:0000269|PubMed:16451135, ECO:0000269|PubMed:17301300, ECO:0000269|PubMed:17510385, ECO:0000269|PubMed:18561205, ECO:0000269|PubMed:20020535, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22753075, ECO:0000269|PubMed:7757073, ECO:0000269|PubMed:8566964, ECO:0000269|PubMed:8571956, ECO:0000269|PubMed:8574961, ECO:0000269|PubMed:8797773, ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:8993976, ECO:0000269|PubMed:9048925, ECO:0000269|PubMed:9067757, ECO:0000269|PubMed:9218993, ECO:0000269|PubMed:9272156, ECO:0000269|PubMed:9298827, ECO:0000269|PubMed:9311737, ECO:0000269|PubMed:9326924, ECO:0000269|PubMed:9399661, ECO:0000269|PubMed:9559627, ECO:0000269|PubMed:9718327, ECO:0000269|PubMed:9833759, ECO:0000269|PubMed:9927034, ECO:0000269|Ref.5}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Mismatch repair cancer syndrome 1 (MMRCS1) [MIM:276300]: An autosomal recessive form of mismatch repair cancer syndrome, a childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. {ECO:0000269|PubMed:11427529, ECO:0000269|PubMed:17440981, ECO:0000269|PubMed:7661930}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. {ECO:0000269|PubMed:8751876}. The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.; DISEASE: Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. Disease susceptibility is associated with variants affecting the gene represented in this entry.; DISEASE: Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by Lynch syndrome but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:10598809, ECO:0000269|PubMed:10882759, ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12655564, ECO:0000269|PubMed:14504054, ECO:0000269|PubMed:15184898, ECO:0000269|PubMed:18033691, ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:9032648, ECO:0000269|PubMed:9087566, ECO:0000269|PubMed:9611074}. Disease susceptibility is associated with variants affecting the gene represented in this entry.

DB09043; DB09045; DB15650; DB01276; DB00040; DB16697; DB06655; DB09265; DB13928; DB14027; DB15171

A8MQ03; Q07627; Q8IUG1; P60409; P60410; P60411; Q9BYP8; P26371; Q7Z3S9; P0DPK4

NA

3D-structure; ADP-ribosylation; Cell membrane; Disulfide bond; G-protein coupled receptor; Glycoprotein; Membrane; Receptor; Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix

R

45579.6

390

0.16

39.66

6.73

-0.68

-10.21