HPD (4-hydroxyphenylpyruvate dioxygenase)

Gene

• Entrez ID: 3242
• Gene name: 4-hydroxyphenylpyruvate dioxygenase
• Gene symbol: HPD
• Synonyms (NCBI Gene): 4-HPPD, 4HPPD, GLOD3, HPPD, HPPDASE, PPD
• Chromosome: 12
• Chromosome location: 12q24.31
• Summary: The protein encoded by this gene is an enzyme in the catabolic pathway of tyrosine. The encoded protein catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. Defects in this gene are a cause of tyrosinemia type 3 (TYRO3) and hawkinsinuria

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs137852865	T>C	Pathogenic	Coding sequence variant, missense variant
rs137852866	A>C	Pathogenic	Coding sequence variant, stop gained
rs137852867	G>C	Pathogenic	Coding sequence variant, stop gained
rs137852868	G>C,T	Conflicting-interpretations-of-pathogenicity, benign, likely-benign, pathogenic	Coding sequence variant, synonymous variant, missense variant
rs1592913789	A>G	Likely-pathogenic	Missense variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT1054105	hsa-miR-3147	CLIP-seq
MIRT1054106	hsa-miR-4259	CLIP-seq
MIRT1054107	hsa-miR-4676-5p	CLIP-seq
MIRT1054108	hsa-miR-575	CLIP-seq

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000139	Component	Golgi membrane	IBA
GO:0000139	Component	Golgi membrane	IEA
GO:0003868	Function	4-hydroxyphenylpyruvate dioxygenase activity	IBA
GO:0003868	Function	4-hydroxyphenylpyruvate dioxygenase activity	IDA	1339442, 31537781
GO:0003868	Function	4-hydroxyphenylpyruvate dioxygenase activity	IEA
GO:0003868	Function	4-hydroxyphenylpyruvate dioxygenase activity	ISS
GO:0005737	Component	Cytoplasm	IEA
GO:0005783	Component	Endoplasmic reticulum	IEA
GO:0005789	Component	Endoplasmic reticulum membrane	IBA
GO:0005789	Component	Endoplasmic reticulum membrane	IEA
GO:0005794	Component	Golgi apparatus	IEA
GO:0005829	Component	Cytosol	TAS
GO:0006559	Process	L-phenylalanine catabolic process	IEA
GO:0006572	Process	L-tyrosine catabolic process	IBA
GO:0006572	Process	L-tyrosine catabolic process	IDA	31537781
GO:0006572	Process	L-tyrosine catabolic process	IEA
GO:0006572	Process	L-tyrosine catabolic process	ISS
GO:0006572	Process	L-tyrosine catabolic process	TAS	7851880
GO:0009072	Process	Aromatic amino acid metabolic process	IEA
GO:0016020	Component	Membrane	IEA
GO:0016491	Function	Oxidoreductase activity	IEA
GO:0016701	Function	Oxidoreductase activity, acting on single donors with incorporation of molecular oxygen	IEA
GO:0042803	Function	Protein homodimerization activity	IDA	1339442
GO:0042803	Function	Protein homodimerization activity	IEA
GO:0046872	Function	Metal ion binding	IEA
GO:0051213	Function	Dioxygenase activity	IEA
GO:0070062	Component	Extracellular exosome	HDA	19056867

Other IDs

• MIM: 609695
• HGNC: 5147
• e!Ensembl: ENSG00000158104

Protein

• UniProt ID: P32754
• Protein name: 4-hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27) (4-hydroxyphenylpyruvic acid oxidase) (4HPPD) (HPD) (HPPDase)
• Protein function: Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.
• PDB: 3ISQ, 5EC3, 8IM2, 8IM3
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF13669	Glyoxalase_4	20 → 134		Family
  PF00903	Glyoxalase	180 → 335	Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily	Domain

• Sequence:

  MTTYSDKGAKPERGRFLHFHSVTFWVGNAKQAASFYCSKMGFEPLAYRGLETGSREVVSH
  VIKQGKIVFVLSSALNPWNKEMGDHLVKHGDGVKDIAFEVEDCDYIVQKARERGAKIMRE
  PWVEQDKFGKVKFAVLQTYGDTTHTLVEKMNYIGQFLPGYEAPAFMDPLLPKLPKCSLEM
  IDHIVGNQPDQEMVSASEWYLKNLQFHRFWSVDDTQVHTEYSSLRSIVVANYEESIKMPI
  NEPAPGKKKSQIQEYVDYNGGAGVQHIALKTEDIITAIRHLRERGLEFLSVPSTYYKQLR
  EKLKTAKIKVKENIDALEELKILVDYDEKGYLLQIFTKPVQDRPTLFLEVIQRHNHQGFG
  AGNFNSLFKAFEEEQNLRGNLTNMETNGVVPGM

• Sequence length: 393

Pathways

KEGG:

Ubiquinone and other terpenoid-quinone biosynthesis
Tyrosine metabolism
Phenylalanine metabolism
Metabolic pathways
Biosynthesis of cofactors

Reactome:

Tyrosine catabolism

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)

Causal
Phenotype Name	Clinical Significance	dbSNP ID	RCV Accession	Evidence Score
Hawkinsinuria	Pathogenic; Likely pathogenic	rs2137631671, rs137852865, rs762267460, rs2500327296, rs2500329137, rs747956311, rs142252243, rs2500298619, rs113472814, rs1386803894, rs2500289881, rs113367095, rs2500331848, rs2500329430, rs2500327527, rs1294210561, rs201751544, rs2500327565, rs2500323693, rs367674632, rs775747384, rs895823217, rs1276998235	RCV001903686 RCV001297386 RCV003077399 RCV003020314 RCV003055865 RCV003778669 RCV003785507 RCV003797856 RCV003782776 RCV003791992 RCV003794655 RCV003806950 RCV003793698 RCV003805774 RCV003794892 RCV003809041 RCV003804767 RCV003804594 RCV003809935 RCV003818114 RCV000634916 RCV000690834 RCV000796401 RCV001226133 RCV001258320	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Tyrosinemia type III	Pathogenic; Likely pathogenic	rs2137619413, rs2137631671, rs137852865, rs137852866, rs137852867, rs762267460, rs2500327296, rs2500329137, rs747956311, rs2500289988, rs2500298650, rs142252243, rs2500298619, rs113472814, rs1386803894, rs2500289881, rs113367095, rs2500331848, rs2500329430, rs2500327527, rs1294210561, rs201751544, rs2500327565, rs2500323693, rs367674632, rs775747384, rs895823217	RCV001808001 RCV001903686 RCV000001639 RCV000001640 RCV000001641 RCV003077399 RCV003020314 RCV003055865 RCV003123426 RCV003155618 RCV003226729 RCV003785507 RCV003797856 RCV003782776 RCV003791992 RCV003794655 RCV003806950 RCV003793698 RCV003805774 RCV003794892 RCV003809041 RCV003804767 RCV003804594 RCV003809935 RCV003818114 RCV000634916 RCV000690834 RCV000796401 RCV001226133	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute myeloid leukemia	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Cholangiocarcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Clear cell carcinoma of kidney	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Familial cancer of breast	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Gastric cancer	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
GLOBAL DEVELOPMENTAL DELAY	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hepatocellular carcinoma	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
HPD-related disorder	Conflicting classifications of pathogenicity; Likely benign; Benign; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Hypertyrosinemia	Uncertain significance; Likely benign; Benign	ClinVar Disgenet	★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Malignant tumor of esophagus	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
OBESITY	—	GWAS catalog	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Ovarian serous cystadenocarcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thymoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Thyroid cancer, nonmedullary, 1	Benign; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYROSINEMIA TYPE 3	—	Orphanet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYROSINEMIA, TYPE III	—	Disgenet, HPO Disgenet, HPO	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
TYROSINEMIAS	—	CTD, Disgenet CTD, Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Alkaptonuria	Alkaptonuria	Pubtator	36985595, 40243989	Associate	★☆☆☆☆ Found in Text Mining only
Amyloidosis cutis dyschromia	Amyloidosis Cutis Dyschromia	BEFREE	28889150		★☆☆☆☆ Found in Text Mining only
Autistic Disorder	Autism	BEFREE	11916331		★☆☆☆☆ Found in Text Mining only
Avellino corneal dystrophy	Avellino Corneal Dystrophy	BEFREE	28889150		★☆☆☆☆ Found in Text Mining only
Breast Carcinoma	Breast Carcinoma	BEFREE	22911819, 31277952		★☆☆☆☆ Found in Text Mining only
Bronchitis, Chronic	Gastric Cancer	BEFREE	9210589		★☆☆☆☆ Found in Text Mining only
Buruli Ulcer	Buruli Ulcer	BEFREE	10756149		★☆☆☆☆ Found in Text Mining only
Carcinoma of lung	Lung carcinoma	BEFREE	31285420		★☆☆☆☆ Found in Text Mining only
Cardiovascular Diseases	Cardiovascular Diseases	BEFREE	15899484		★☆☆☆☆ Found in Text Mining only
Contact Dermatitis	Dermatitis	BEFREE	7233093		★☆☆☆☆ Found in Text Mining only
Depression, Postpartum	Mental Depression	BEFREE	31533685		★☆☆☆☆ Found in Text Mining only
Diabetes Mellitus	Diabetes mellitus	Pubtator	35230239	Associate	★☆☆☆☆ Found in Text Mining only
Dystonia Disorders	Dystonia	BEFREE	10079965		★☆☆☆☆ Found in Text Mining only
FG syndrome	FG Syndrome	BEFREE	9475086		★☆☆☆☆ Found in Text Mining only
Fibrosis, Liver	Liver Fibrosis	BEFREE	29929367		★☆☆☆☆ Found in Text Mining only
Greig cephalopolysyndactyly syndrome	Greig Cephalopolysyndactyly Syndrome	BEFREE	22903559		★☆☆☆☆ Found in Text Mining only
Hawkinsinuria	Hawkinsinuria	GENOMICS_ENGLAND_DG	10942115, 17560158		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hawkinsinuria	Hawkinsinuria	BEFREE	11073718, 20677779, 26226126, 31054541		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hawkinsinuria	Hawkinsinuria	ORPHANET_DG	11073718, 17560158		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hawkinsinuria	Hawkinsinuria	Orphanet			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hawkinsinuria	Hawkinsinuria	CTD_human_DG			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hawkinsinuria	Hawkinsinuria	CLINVAR_DG			★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Hypercholesterolemia, Familial	Hypercholesterolemia	BEFREE	15026427, 15899484		★☆☆☆☆ Found in Text Mining only
Hyperlipoproteinemia Type IIa	Hyperlipoproteinemia	BEFREE	15026427, 15899484		★☆☆☆☆ Found in Text Mining only
Hyperphenylalaninaemia	Hyperphenylalaninemia	BEFREE	9667588		★☆☆☆☆ Found in Text Mining only
Hypertyrosinemia	Hypertyrosinemia	BEFREE	31277952		★★★☆☆ Reported in Unknown/Other Associations (≥2 sources)
Hypothyroidism	Hypothyroidism	HPO_DG			★☆☆☆☆ Found in Text Mining only
Liver Cirrhosis	Liver Cirrhosis	BEFREE	1383656		★☆☆☆☆ Found in Text Mining only
Lymphadenitis	Lymphadenitis	BEFREE	30055739		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of breast	Breast Cancer	BEFREE	22911819, 31277952		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of liver	Liver Cancer	BEFREE	1383656		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of lung	Lung Cancer	BEFREE	31285420		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of pancreas	Pancreatic cancer	BEFREE	19203832		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of prostate	Prostate cancer	BEFREE	18253123		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of stomach	Stomach Neoplasms	BEFREE	26428367, 31696031		★☆☆☆☆ Found in Text Mining only
Malignant Neoplasms	Malignant Neoplasm	BEFREE	27827313, 31285420, 31382131		★☆☆☆☆ Found in Text Mining only
Metabolic Diseases	Metabolic syndrome	Pubtator	31578365	Associate	★☆☆☆☆ Found in Text Mining only
Metabolic Syndrome	Metabolic syndrome	Pubtator	35230239	Associate	★☆☆☆☆ Found in Text Mining only
Mild Mental Retardation	Mental retardation	HPO_DG			★☆☆☆☆ Found in Text Mining only
Mood Disorders	Mood Disorder	BEFREE	8297808		★☆☆☆☆ Found in Text Mining only
Neoplasms	Neoplasms	BEFREE	18253123, 27827313, 29473838, 31285420, 31571900		★☆☆☆☆ Found in Text Mining only
Non-Small Cell Lung Carcinoma	Lung carcinoma	BEFREE	31571900		★☆☆☆☆ Found in Text Mining only
Osteopenia	Osteopenia	BEFREE	29843053, 30389428		★☆☆☆☆ Found in Text Mining only
Pallister-Hall syndrome	Pallister-Hall Syndrome	BEFREE	10441570, 22903559		★☆☆☆☆ Found in Text Mining only
Pancreatic carcinoma	Pancreatic carcinoma	BEFREE	19203832		★☆☆☆☆ Found in Text Mining only
Paratuberculosis	Paratuberculosis	BEFREE	29483289		★☆☆☆☆ Found in Text Mining only
Parkinson Disease	Parkinson disease	BEFREE	23485738		★☆☆☆☆ Found in Text Mining only
Periodontal Diseases	Periodontal Diseases	BEFREE	25280920, 27727278		★☆☆☆☆ Found in Text Mining only
Polydactyly	Polydactyly	BEFREE	12837695		★☆☆☆☆ Found in Text Mining only
POLYDACTYLY, POSTAXIAL	Polydactyly	BEFREE	15811011		★☆☆☆☆ Found in Text Mining only
Progressive pseudorheumatoid dysplasia	Progressive Pseudorheumatoid Dysplasia	BEFREE	28802407, 29312328, 30096296		★☆☆☆☆ Found in Text Mining only
Prostate carcinoma	Prostate cancer	BEFREE	18253123		★☆☆☆☆ Found in Text Mining only
Radial polydactyly	Radial Polydactyly	BEFREE	15811011		★☆☆☆☆ Found in Text Mining only
Respiratory Tract Diseases	Respiratory system infectious disease	Pubtator	35552657	Associate	★☆☆☆☆ Found in Text Mining only
Schizophrenia	Schizophrenia	BEFREE	8297808		★☆☆☆☆ Found in Text Mining only
Skin-picking	Skin-picking	BEFREE	30446196		★☆☆☆☆ Found in Text Mining only
Stomach Carcinoma	Stomach Carcinoma	BEFREE	26428367, 31696031		★☆☆☆☆ Found in Text Mining only
Syndactyly	Syndactyly	BEFREE	15811011		★☆☆☆☆ Found in Text Mining only
Tyrosine Transaminase Deficiency Disease	Tyrosinemia	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Tyrosinemia type 3	Tyrosinemia	Orphanet			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type I	Tyrosinemia	BEFREE	12127941, 20003495, 28637410, 30231914, 30297903, 30684868		★☆☆☆☆ Found in Text Mining only
Tyrosinemia, Type I	Tyrosinemia	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Tyrosinemia, Type III	Tyrosinemia	BEFREE	10942115, 11073718, 12127941, 23036342, 31054541		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	CLINGEN_DG	10942115, 11073718, 23036342, 4627454, 7774914, 8989996		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	GENOMICS_ENGLAND_DG	10942115, 17560158		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	UNIPROT_DG	10942115, 11073718		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	ORPHANET_DG	10942115		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	CLINVAR_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemia, Type III	Tyrosinemia	CTD_human_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemias	Tyrosinemia	BEFREE	16896227, 28755195, 30297903, 31277952		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemias	Tyrosinemia	Pubtator	16896227	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemias	Tyrosinemia	HPO_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Tyrosinemias	Tyrosinemia	CTD_human_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations