PPOX (protoporphyrinogen oxidase)

Gene

• Entrez ID: 5498
• Gene name: Protoporphyrinogen oxidase
• Gene symbol: PPOX
• Synonyms (NCBI Gene): PPO, V290M, VP, VPCO
• Chromosome: 1
• Chromosome location: 1q23.3
• Summary: This gene encodes the penultimate enzyme of heme biosynthesis, which catalyzes the 6-electron oxidation of protoporphyrinogen IX to form protoporphyrin IX. Mutations in this gene cause variegate porphyria, an autosomal dominant disorder of heme metabolism

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs12735723	C>G,T	Pathogenic, benign, uncertain-significance	Coding sequence variant, intron variant, missense variant, non coding transcript variant
rs28936676	A>C	Pathogenic	Coding sequence variant, intron variant, missense variant, non coding transcript variant
rs28936677	T>C	Pathogenic	Genic upstream transcript variant, coding sequence variant, 5 prime UTR variant, missense variant, upstream transcript variant, non coding transcript variant
rs41270025	G>A,T	Pathogenic	Coding sequence variant, intron variant, missense variant, non coding transcript variant
rs121918323	G>C	Pathogenic	Missense variant, coding sequence variant, 5 prime UTR variant, intron variant, non coding transcript variant
rs121918324	C>T	Pathogenic	Missense variant, coding sequence variant, 5 prime UTR variant, upstream transcript variant, genic upstream transcript variant, non coding transcript variant
rs121918325	C>T	Pathogenic	Non coding transcript variant, missense variant, intron variant, coding sequence variant
rs121918326	A>C	Pathogenic	Missense variant, coding sequence variant, 5 prime UTR variant, upstream transcript variant, genic upstream transcript variant, non coding transcript variant
rs762280759	C>A,T	Pathogenic	Synonymous variant, coding sequence variant, stop gained, non coding transcript variant, genic upstream transcript variant, upstream transcript variant, 5 prime UTR variant
rs786204784	C>-	Pathogenic	Coding sequence variant, genic upstream transcript variant, 5 prime UTR variant, stop gained, upstream transcript variant, non coding transcript variant
rs956668146	C>T	Pathogenic	Coding sequence variant, stop gained, non coding transcript variant, intron variant
rs1558033572	TA>-	Likely-pathogenic	Splice acceptor variant, intron variant
rs1571325144	T>C	Pathogenic	Coding sequence variant, genic upstream transcript variant, missense variant, 5 prime UTR variant, upstream transcript variant, initiator codon variant, non coding transcript variant
rs1571352321	C>T	Pathogenic	Coding sequence variant, intron variant, missense variant, 5 prime UTR variant, synonymous variant, non coding transcript variant
rs1571357779	AT>-	Pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant, intron variant
rs1571369150	->G	Pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant, intron variant
rs1571406458	AG>-	Pathogenic	Frameshift variant, coding sequence variant, non coding transcript variant, intron variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT028501	hsa-miR-30a-5p	Proteomics	18668040
MIRT2457056	hsa-miR-2110	CLIP-seq
MIRT2457057	hsa-miR-3150a-3p	CLIP-seq
MIRT2457058	hsa-miR-4259	CLIP-seq
MIRT2457059	hsa-miR-433	CLIP-seq
MIRT2457060	hsa-miR-4693-3p	CLIP-seq
MIRT2457061	hsa-miR-4712-3p	CLIP-seq
MIRT2457062	hsa-miR-571	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
GATA1	Unknown	18191920

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0004729	Function	Oxygen-dependent protoporphyrinogen oxidase activity	IBA
GO:0004729	Function	Oxygen-dependent protoporphyrinogen oxidase activity	IDA	7713909, 21048046
GO:0004729	Function	Oxygen-dependent protoporphyrinogen oxidase activity	IEA
GO:0005739	Component	Mitochondrion	HTP	34800366
GO:0005739	Component	Mitochondrion	IEA
GO:0005743	Component	Mitochondrial inner membrane	IBA
GO:0005743	Component	Mitochondrial inner membrane	IEA
GO:0005743	Component	Mitochondrial inner membrane	ISS
GO:0005758	Component	Mitochondrial intermembrane space	IEA
GO:0005758	Component	Mitochondrial intermembrane space	IEA
GO:0005758	Component	Mitochondrial intermembrane space	TAS
GO:0006779	Process	Porphyrin-containing compound biosynthetic process	IDA	7713909
GO:0006779	Process	Porphyrin-containing compound biosynthetic process	IEA
GO:0006782	Process	Protoporphyrinogen IX biosynthetic process	IEA
GO:0006783	Process	Heme biosynthetic process	IBA
GO:0006783	Process	Heme biosynthetic process	IDA	7713909
GO:0006783	Process	Heme biosynthetic process	IEA
GO:0006783	Process	Heme biosynthetic process	IEA
GO:0006784	Process	Heme A biosynthetic process	IEA
GO:0006785	Process	Heme B biosynthetic process	IDA	7713909
GO:0006785	Process	Heme B biosynthetic process	IEA
GO:0009410	Process	Response to xenobiotic stimulus	IEA
GO:0016020	Component	Membrane	IEA
GO:0016491	Function	Oxidoreductase activity	IEA
GO:0031966	Component	Mitochondrial membrane	IEA
GO:0031966	Component	Mitochondrial membrane	IMP	7713909
GO:0046501	Process	Protoporphyrinogen IX metabolic process	IEA
GO:0048034	Process	Heme O biosynthetic process	IEA
GO:0050660	Function	Flavin adenine dinucleotide binding	TAS	7713909

Other IDs

• MIM: 600923
• HGNC: 9280
• e!Ensembl: ENSG00000143224

Protein

• UniProt ID: P50336
• Protein name: Protoporphyrinogen oxidase (PPO) (EC 1.3.3.4)
• Protein function: Catalyzes the 6-electron oxidation of protoporphyrinogen-IX to form protoporphyrin-IX.
• PDB: 3NKS, 4IVM, 4IVO
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF01593	Amino_oxidase	12 → 471	Flavin containing amine oxidoreductase	Domain

• Tissue specificity: TISSUE SPECIFICITY: Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. {ECO:0000269|PubMed:8771201}.
• Sequence:

  MGRTVVVLGGGISGLAASYHLSRAPCPPKVVLVESSERLGGWIRSVRGPNGAIFELGPRG
  IRPAGALGARTLLLVSELGLDSEVLPVRGDHPAAQNRFLYVGGALHALPTGLRGLLRPSP
  PFSKPLFWAGLRELTKPRGKEPDETVHSFAQRRLGPEVASLAMDSLCRGVFAGNSRELSI
  RSCFPSLFQAEQTHRSILLGLLLGAGRTPQPDSALIRQALAERWSQWSLRGGLEMLPQAL
  ETHLTSRGVSVLRGQPVCGLSLQAEGRWKVSLRDSSLEADHVISAIPASVLSELLPAEAA
  PLARALSAITAVSVAVVNLQYQGAHLPVQGFGHLVPSSEDPGVLGIVYDSVAFPEQDGSP
  PGLRVTVMLGGSWLQTLEASGCVLSQELFQQRAQEAAATQLGLKEMPSHCLVHLHKNCIP
  QYTLGHWQKLESARQFLTAHRLPLTLAGASYEGVAVNDCIESGRQAAVSVLGTEPNS

• Sequence length: 477

Pathways

KEGG:

Porphyrin metabolism
Metabolic pathways
Biosynthesis of cofactors

Reactome:

Heme biosynthesis

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
Abdominal colic	Likely pathogenic	rs1057518798	RCV000415419	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Abnormal blistering of the skin	Likely pathogenic; Pathogenic	rs1057518798, rs148292941	RCV000415419 RCV000626658	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Abnormal urinary color	Pathogenic	rs148292941	RCV000626658	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Abnormality of metabolism/homeostasis	Likely pathogenic	rs2101886463	RCV001814441	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Cardiomyopathy	Likely pathogenic; Pathogenic	rs2525306943	RCV006255220	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Cervical cancer	Likely pathogenic	rs999497211	RCV005930670	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Constipation	Pathogenic	rs148292941	RCV000626658	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Hepatocellular carcinoma	Pathogenic	rs2101862742	RCV005868483	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Migraine	Pathogenic	rs148292941	RCV000626658	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Porphyrinuria	Likely pathogenic	rs1057518798	RCV000415419	★★★★☆ ClinVar: Pathogenic / Likely Pathogenic (<5 Variants)
Variegate porphyria	Pathogenic; Likely pathogenic	rs2525204882, rs786204784, rs121918323, rs121918325, rs121918326, rs121918324, rs41270025, rs1571357779, rs2101902523, rs28936677, rs1659156571, rs1558033572, rs1571369150, rs1571418365	RCV002281665 RCV000169672 RCV000009230 RCV000009231 RCV000009232 RCV000009233 RCV000009234 RCV000009236 RCV000009237 RCV003324494 RCV003993553 RCV000761331 RCV002271591 RCV001253784	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Variegate porphyria, childhood-onset	Likely pathogenic; Pathogenic	rs121918325, rs121918324, rs28936676, rs2101876868, rs28936677, rs2525249140, rs900431442, rs767419411, rs2525294446	RCV003324488 RCV003324489 RCV003324490 RCV003324491 RCV003324495 RCV003324652 RCV003324654 RCV003324655 RCV003324656	★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)

Unknown / Other Associations
Phenotype Name	Clinical Significance	Source	Evidence Score
Acute intermittent porphyria	Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Acute myeloid leukemia	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
COLORECTAL NEOPLASMS	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
MIGRAINE DISORDERS	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PORPHYRIA, VARIEGATE	—	CTD	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PORPHYRURIA	—	Disgenet	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
PPOX-related disorder	Likely benign; Conflicting classifications of pathogenicity; Uncertain significance	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Sarcoma	Uncertain significance; Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Uterine corpus endometrial carcinoma	Likely benign	ClinVar	★★☆☆☆ Found in Text Mining + Unknown/Other Associations

Associations from Text Mining
Disease Name	Disease (Merged)	Source	PMID	Relationship Type	Evidence Score
Acute intermittent porphyria	Intermittent Porphyria	BEFREE	12699245, 12899439, 14669009, 25445397		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Anemia	Anemia	BEFREE	25090246		★☆☆☆☆ Found in Text Mining only
Anxiety	Anxiety Disorder	HPO_DG			★☆☆☆☆ Found in Text Mining only
Atrial Fibrillation	Atrial Fibrillation	BEFREE	30098034		★☆☆☆☆ Found in Text Mining only
Carcinoma Hepatocellular	Hepatocellular carcinoma	Pubtator	20814629	Associate	★☆☆☆☆ Found in Text Mining only
Colon Carcinoma	Colon Carcinoma	BEFREE	25944804		★☆☆☆☆ Found in Text Mining only
Colorectal Carcinoma	Colorectal Cancer	CTD_human_DG	25944804		★☆☆☆☆ Found in Text Mining only
Colorectal Neoplasms	Colorectal Neoplasms	CTD_human_DG	25944804		★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Coproporphyria Hereditary	Hereditary coproporphyria	Pubtator	21734717, 31073229	Associate	★☆☆☆☆ Found in Text Mining only
Depressive disorder	Mental Depression	HPO_DG			★☆☆☆☆ Found in Text Mining only
Disorders of Porphyrin Metabolism	Porphyria	BEFREE	12699245, 14669009, 15660919, 21734717, 9074790		★☆☆☆☆ Found in Text Mining only
Erythropoietic Protoporphyria	Erythropoietic Protoporphyria	BEFREE	12699245		★☆☆☆☆ Found in Text Mining only
Glomerulonephritis IGA	Iga nephropathy	Pubtator	11286631	Associate	★☆☆☆☆ Found in Text Mining only
Hereditary Coproporphyria	Hereditary Coproporphyria	BEFREE	14669009		★☆☆☆☆ Found in Text Mining only
Homozygous variegate porphyria	Homozygous Variegate Porphyria	BEFREE	3319294		★☆☆☆☆ Found in Text Mining only
Homozygous variegate porphyria	Homozygous Variegate Porphyria	CLINVAR_DG			★☆☆☆☆ Found in Text Mining only
Hydroxymethylbilane Synthase Deficiency	Hydroxymethylbilane Synthase Deficiency	BEFREE	11800145		★☆☆☆☆ Found in Text Mining only
Hypogonadism, Isolated Hypogonadotropic	Hypogonadism	BEFREE	28882981		★☆☆☆☆ Found in Text Mining only
Liver carcinoma	Liver carcinoma	BEFREE	25445397		★☆☆☆☆ Found in Text Mining only
Malignant neoplasm of liver	Liver Cancer	BEFREE	25445397		★☆☆☆☆ Found in Text Mining only
Malignant tumor of colon	Colonic Neoplasms	BEFREE	25944804		★☆☆☆☆ Found in Text Mining only
Peripheral Nervous System Diseases	Nervous System Diseases	HPO_DG			★☆☆☆☆ Found in Text Mining only
Polyneuropathy, Motor	Polyneuropathy	HPO_DG			★☆☆☆☆ Found in Text Mining only
Porphobilinogen synthase deficiency	Porphobilinogen Synthase Deficiency	BEFREE	20814629, 7586575, 8852667		★☆☆☆☆ Found in Text Mining only
Porphyria Acute Intermittent	Porphyria	Pubtator	27788171	Stimulate	★☆☆☆☆ Found in Text Mining only
Porphyria Acute Intermittent	Porphyria	Pubtator	31073229	Associate	★☆☆☆☆ Found in Text Mining only
Porphyria variegata	Variegate porphyria	Orphanet			★☆☆☆☆ Found in Text Mining only
Porphyria Variegate	Variegate porphyria	Pubtator	10486317, 11286631, 17298217, 18570668, 20331452, 20814629, 21734717, 23324528, 23467411, 27746433, 28653968, 29516370, 31073229, 34968794, 36224252	Associate	★☆☆☆☆ Found in Text Mining only
Porphyria Variegate	Variegate porphyria	Pubtator	11800145, 27788171	Inhibit	★☆☆☆☆ Found in Text Mining only
Porphyria, South African type	Porphyria	CTD_human_DG			★☆☆☆☆ Found in Text Mining only
Porphyrias	Porphyria	Pubtator	21734717	Associate	★☆☆☆☆ Found in Text Mining only
Porphyrias, Hepatic	Hepatic porphyria	LHGDN	14669009		★☆☆☆☆ Found in Text Mining only
Porphyruria	Porphyruria	HPO_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Porphyruria	Porphyruria	CLINVAR_DG			★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Psychotic Disorders	Psychosis	HPO_DG			★☆☆☆☆ Found in Text Mining only
Sarcoma	Sarcoma	Pubtator	38316340	Associate	★★☆☆☆ Found in Text Mining + Unknown/Other Associations
Skin Diseases	Skin disease	Pubtator	29130490, 29516370	Associate	★☆☆☆☆ Found in Text Mining only
Stomach Neoplasms	Stomach neoplasms	Pubtator	29425880	Associate	★☆☆☆☆ Found in Text Mining only
Variegate Porphyria	Variegate Porphyria	BEFREE	10401000, 10457135, 11474578, 11929051, 11930946, 12357337, 12655566, 12699245, 12859407, 12899439, 14976149, 15660919, 16433813, 16922948, 16947091, 17298217, 18550261, 18570668, 19656457, 21734717, 21910705, 23324528, 23467411, 23601071, 25445397, 27667166, 2864531, 28654958, 29516370, 3015635, 30476629, 7327566, 7586575, 8634714, 8673113, 8817334, 8852667, 9003509, 9074790, 9540990, 9541112, 9738863, 9763307, 9778454, 9811936		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Variegate Porphyria	Variegate Porphyria	UNIPROT_DG	10486317, 10870850, 11074242, 11102990, 11286631, 11348478, 11350188, 11474578, 12380696, 12655566, 12859407, 12922165, 14669009, 16433813, 16621625, 16922948, 16947091, 18350656, 18570668, 19320019, 21048046, 23430901, 23467411, 24073655, 8673113, 8817334, 8852667, 9541112, 9763307, 9811936		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Variegate Porphyria	Variegate Porphyria	CLINVAR_DG	10486317, 11298551, 1946837		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Variegate Porphyria	Variegate Porphyria	LHGDN	16947091		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)
Variegate Porphyria	Variegate Porphyria	GENOMICS_ENGLAND_DG	9811936		★★★★★ ClinVar: Pathogenic / Likely Pathogenic (≥5 Variants)