AKR1C4 (aldo-keto reductase family 1 member C4)

Gene

• Entrez ID: 1109
• Gene name: Aldo-keto reductase family 1 member C4
• Gene symbol: AKR1C4
• Synonyms (NCBI Gene): 3-alpha-HSD, C11, CDR, CHDR, DD-4, DD4, HAKRA
• Chromosome: 10
• Chromosome location: 10p15.1
• Summary: This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs398122815	G>T	Risk-factor	Intron variant

Transcription factors

Transcription factor	Regulation	Reference
HNF1A	Unknown	11284743
HNF4A	Unknown	11284743
HNF4G	Unknown	11284743

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001523	Process	Retinoid metabolic process	TAS
GO:0001758	Function	Retinal dehydrogenase (NAD+) activity	IDA	21851338
GO:0004032	Function	Aldose reductase (NADPH) activity	IBA
GO:0004303	Function	Estradiol 17-beta-dehydrogenase [NAD(P)+] activity	IEA
GO:0005515	Function	Protein binding	IPI	28514442, 33961781
GO:0005737	Component	Cytoplasm	IEA
GO:0005737	Component	Cytoplasm	TAS	2187532
GO:0005829	Component	Cytosol	IBA
GO:0005829	Component	Cytosol	IEA
GO:0005829	Component	Cytosol	TAS
GO:0006066	Process	Alcohol metabolic process	IEA
GO:0006629	Process	Lipid metabolic process	IEA
GO:0006693	Process	Prostaglandin metabolic process	IBA
GO:0006699	Process	Bile acid biosynthetic process	TAS
GO:0008106	Function	Alcohol dehydrogenase (NADP+) activity	TAS	7650035
GO:0008202	Process	Steroid metabolic process	IEA
GO:0008202	Process	Steroid metabolic process	TAS	8274401
GO:0008209	Process	Androgen metabolic process	TAS	7650035
GO:0009055	Function	Electron transfer activity	TAS	8172617
GO:0015125	Function	Bile acid transmembrane transporter activity	TAS	8172617
GO:0015721	Process	Bile acid and bile salt transport	TAS	8172617
GO:0016491	Function	Oxidoreductase activity	IEA
GO:0016655	Function	Oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor	IDA	20837989
GO:0032052	Function	Bile acid binding	IBA
GO:0032787	Process	Monocarboxylic acid metabolic process	IEA
GO:0042445	Process	Hormone metabolic process	IEA
GO:0042448	Process	Progesterone metabolic process	IBA
GO:0044597	Process	Daunorubicin metabolic process	IBA
GO:0044597	Process	Daunorubicin metabolic process	IMP	20837989
GO:0044598	Process	Doxorubicin metabolic process	IBA
GO:0044598	Process	Doxorubicin metabolic process	IMP	20837989
GO:0047023	Function	Androsterone dehydrogenase [NAD(P)+] activity	IBA
GO:0047023	Function	Androsterone dehydrogenase [NAD(P)+] activity	IDA	21851338
GO:0047023	Function	Androsterone dehydrogenase [NAD(P)+] activity	IEA
GO:0047024	Function	5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) activity	IEA
GO:0047035	Function	Testosterone dehydrogenase (NAD+) activity	IEA
GO:0047044	Function	Androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity	IEA
GO:0047045	Function	Testosterone dehydrogenase (NADP+) activity	IEA
GO:0047086	Function	Ketosteroid monooxygenase activity	IBA
GO:0047743	Function	Chlordecone reductase activity	IDA	2427522
GO:0047743	Function	Chlordecone reductase activity	IEA
GO:0070062	Component	Extracellular exosome	HDA	23533145
GO:0071395	Process	Cellular response to jasmonic acid stimulus	IDA	19487289

Other IDs

• MIM: 600451
• HGNC: 387
• e!Ensembl: ENSG00000198610

Protein

• UniProt ID: P17516
• Protein name: Aldo-keto reductase family 1 member C4 (EC 1.1.1.-) (EC 1.1.1.209) (EC 1.1.1.210) (EC 1.1.1.51) (EC 1.1.1.53) (EC 1.1.1.62) (3-alpha-hydroxysteroid dehydrogenase type I) (3-alpha-HSD1) (EC 1.1.1.357) (3alpha-hydroxysteroid 3-dehydrogenase) (Chlordecone re
• Protein function: Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver specific enzyme that acts as an NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and sid
• PDB: 2FVL
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00248	Aldo_ket_red	18 → 301	Aldo/keto reductase family	Domain

• Tissue specificity: TISSUE SPECIFICITY: Liver specific. {ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055, ECO:0000269|PubMed:7650035}.
• Sequence:

  MDPKYQRVELNDGHFMPVLGFGTYAPPEVPRNRAVEVTKLAIEAGFRHIDSAYLYNNEEQ
  VGLAIRSKIADGSVKREDIFYTSKLWCTFFQPQMVQPALESSLKKLQLDYVDLYLLHFPM
  ALKPGETPLPKDENGKVIFDTVDLSATWEVMEKCKDAGLAKSIGVSNFNCRQLEMILNKP
  GLKYKPVCNQVECHPYLNQSKLLDFCKSKDIVLVAHSALGTQRHKLWVDPNSPVLLEDPV
  LCALAKKHKQTPALIALRYQLQRGVVVLAKSYNEQRIRENIQVFEFQLTSEDMKVLDGLN
  RNYRYVVMDFLMDHPDYPFSDEY

• Sequence length: 323

Pathways

KEGG:

Primary bile acid biosynthesis
Steroid hormone biosynthesis
Metabolic pathways
Chemical carcinogenesis - reactive oxygen species

Reactome:

Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol
Synthesis of bile acids and bile salts via 24-hydroxycholesterol
Synthesis of bile acids and bile salts via 27-hydroxycholesterol
Retinoid metabolism and transport

Associated diseases

Evidence Score:

• ★☆☆☆☆  Gene-disease association found in Text Mining only
• ★★☆☆☆  Found in Text Mining and Unknown/Other Associations
• ★★★☆☆  Reported in Unknown/Other Associations across ≥2 Sources
• ★★★★☆  ClinVar: Pathogenic/Likely Pathogenic (<5 Variants)
• ★★★★★  ClinVar: Pathogenic/Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
17 ALPHA-HYDROXYPROGESTERONE ALDOLASE DEFICIENCY	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	risk factor	ClinVar GenCC	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
AKR1C4-related disorder	Uncertain significance; Likely benign; Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
AUTISM SPECTRUM DISORDER	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
BIPOLAR DISORDER	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HYPOGONADISM	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hypotension	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MALE PSEUDOHERMAPHRODITISM DUE TO DEFICIENCY OF TESTICULAR 17,20-DESMOLASE	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PARANOID DISORDERS	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
46, XY Disorders of Sex Development	46, XY disorder of sex development	BEFREE	21802064		★☆☆☆☆ Found in Text Mining only
46,XY disorder of sex development due to testicular 17,20-desmolase deficiency	46, XY disorder of sex development	Orphanet			★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Alzheimer disease, familial, type 3	Alzheimer disease	BEFREE	12766793		★☆☆☆☆ Found in Text Mining only
Ambiguous Genitalia	Ambiguous Genitalia	HPO_DG			★☆☆☆☆ Found in Text Mining only
Amyloidosis	Amyloidosis	BEFREE	29159051		★☆☆☆☆ Found in Text Mining only
Androgenetic Alopecia	Androgenetic Alopecia	BEFREE	26923074		★☆☆☆☆ Found in Text Mining only
Anemia	Anemia	BEFREE	26034358		★☆☆☆☆ Found in Text Mining only
Angle Closure Glaucoma	Angle Closure Glaucoma	BEFREE	30632412		★☆☆☆☆ Found in Text Mining only
Autistic Disorder	Autism	Pubtator	34728519	Associate	★☆☆☆☆ Found in Text Mining only
Behavioral variant of frontotemporal dementia	Behavioral Variant Of Frontotemporal Dementia	BEFREE	28975068		★☆☆☆☆ Found in Text Mining only
Bipolar Disorder	Bipolar Disorder	BEFREE	21570127		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Bipolar Disorder	Bipolar Disorder	PSYGENET_DG	21570127, 22356824		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Bipolar Disorder	Bipolar Disorder	CTD_human_DG	21570127		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Bladder Neoplasm	Bladder Neoplasm	BEFREE	21323680		★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	24260134		★☆☆☆☆ Found in Text Mining only
Breast Neoplasms	Breast neoplasm	Pubtator	40721470	Associate	★☆☆☆☆ Found in Text Mining only
Carcinogenesis	Carcinogenesis	Pubtator	37588985	Associate	★☆☆☆☆ Found in Text Mining only
Carcinoma of bladder	Bladder carcinoma	BEFREE	21323680		★☆☆☆☆ Found in Text Mining only
Chronic Lymphocytic Leukemia	Lymphocytic Leukemia	BEFREE	21525382		★☆☆☆☆ Found in Text Mining only
Cognition Disorders	Cognitive disorder	BEFREE	26147946, 29304923		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal neoplasm	Pubtator	24146633	Associate	★☆☆☆☆ Found in Text Mining only
Cryptorchidism	Cryptorchidism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Dementia	Dementia	BEFREE	23861893, 27464599, 28614836, 30570090, 31547719, 31710340		★☆☆☆☆ Found in Text Mining only
Depression, Bipolar	Bipolar Disorder	CTD_human_DG	21570127		★☆☆☆☆ Found in Text Mining only
Depressive disorder	Mental Depression	BEFREE	29089886		★☆☆☆☆ Found in Text Mining only
Dissection of aorta	Aortic dissection	BEFREE	29290819		★☆☆☆☆ Found in Text Mining only
Frontotemporal Lobar Degeneration	Frontotemporal dementia	BEFREE	31315971, 31620075		★☆☆☆☆ Found in Text Mining only
Glaucoma	Glaucoma	BEFREE	29980724, 30632412		★☆☆☆☆ Found in Text Mining only
Hypertensive disease	Hypertension	BEFREE	30277152		★☆☆☆☆ Found in Text Mining only
Hypospadias	Hypospadias	Pubtator	24986825	Associate	★☆☆☆☆ Found in Text Mining only
Impaired cognition	Impaired Cognition	BEFREE	17845826, 21526197, 24012374, 26147946, 31822312		★☆☆☆☆ Found in Text Mining only
leukemia	Leukemia	BEFREE	10076566		★☆☆☆☆ Found in Text Mining only
Leukemia, Myelocytic, Acute	Leukemia	BEFREE	8142622, 8570222		★☆☆☆☆ Found in Text Mining only
Lung Neoplasms	Lung neoplasms	Pubtator	21544809	Associate	★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus	Lupus Erythematosus	BEFREE	28166678		★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus, Discoid	Lupus Erythematosus	BEFREE	28166678		★☆☆☆☆ Found in Text Mining only
Lupus Erythematosus, Systemic	Lupus Erythematosus	BEFREE	28166678		★☆☆☆☆ Found in Text Mining only
Lupus Vulgaris	Lupus Vulgaris	BEFREE	28166678		★☆☆☆☆ Found in Text Mining only
Lymphoma, Follicular	Lymphoma	BEFREE	8324224		★☆☆☆☆ Found in Text Mining only
Male Pseudohermaphroditism	Male Pseudohermaphroditism	HPO_DG			★☆☆☆☆ Found in Text Mining only
MALE PSEUDOHERMAPHRODITISM: DEFICIENCY OF TESTICULAR 17,20-DESMOLASE	46, XY Sex Reversal	ORPHANET_DG	21802064		★☆☆☆☆ Found in Text Mining only
MALE PSEUDOHERMAPHRODITISM: DEFICIENCY OF TESTICULAR 17,20-DESMOLASE	46, XY Sex Reversal	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
MALE PSEUDOHERMAPHRODITISM: DEFICIENCY OF TESTICULAR 17,20-DESMOLASE	46, XY Sex Reversal	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	24260134		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of liver	Liver Cancer	BEFREE	31611960		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of urinary bladder	Urinary bladder cancer	BEFREE	21323680		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	28259989, 31611960		★☆☆☆☆ Found in Text Mining only
Manic	Manic Disorder	BEFREE	21570127, 22356824		★☆☆☆☆ Found in Text Mining only
Manic	Manic Disorder	CTD_human_DG	21570127		★☆☆☆☆ Found in Text Mining only
Manic Disorder	Manic Disorder	CTD_human_DG	21570127		★☆☆☆☆ Found in Text Mining only
Mental Depression	Mental Depression	BEFREE	29089886		★☆☆☆☆ Found in Text Mining only
Mild cognitive disorder	Cognitive disorder	BEFREE	26842588, 27590706, 27590747, 28287184, 28614836, 30252906		★☆☆☆☆ Found in Text Mining only
Mobius Syndrome	Mobius Syndrome	BEFREE	1708201		★☆☆☆☆ Found in Text Mining only
Nasopharyngeal Carcinoma	Nasopharyngeal carcinoma	Pubtator	35953777	Associate	★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	16966263		★☆☆☆☆ Found in Text Mining only
Osteoporosis	Osteoporosis	BEFREE	31547719		★☆☆☆☆ Found in Text Mining only
Pancreatic Neoplasms	Pancreatic neoplasm	Pubtator	37588985	Associate	★☆☆☆☆ Found in Text Mining only
Paranoia	Paranoia	BEFREE	22356824		★☆☆☆☆ Found in Text Mining only
Paranoia	Paranoia	CTD_human_DG	22356824		★☆☆☆☆ Found in Text Mining only
Parkinsonian Disorders	Parkinson Disease	BEFREE	21422909		★☆☆☆☆ Found in Text Mining only
Polycythemia Vera	Polycythemia Vera	BEFREE	11380400		★☆☆☆☆ Found in Text Mining only
Presenile dementia	Senile Dementia	BEFREE	23861893, 27464599, 28614836, 30570090, 31547719, 31710340		★☆☆☆☆ Found in Text Mining only
Primary angle-closure glaucoma	Angle closure glaucoma	BEFREE	30632412		★☆☆☆☆ Found in Text Mining only
Primary Ciliary Dyskinesia	Ciliary dyskinesia	BEFREE	9006982		★☆☆☆☆ Found in Text Mining only
Prostatic Neoplasms	Prostatic neoplasm	Pubtator	23524847	Associate	★☆☆☆☆ Found in Text Mining only
Senile Plaques	Senile Plaques	BEFREE	17845826		★☆☆☆☆ Found in Text Mining only
SMITH-MCCORT DYSPLASIA 1	Smith-McCort Dysplasia	BEFREE	29290819		★☆☆☆☆ Found in Text Mining only
Thrombocythemia, Essential	Thrombocythemia	BEFREE	11380400		★☆☆☆☆ Found in Text Mining only
Urinary Bladder Neoplasms	Urinary bladder neoplasms	Pubtator	21323680	Associate	★☆☆☆☆ Found in Text Mining only