HPGD

protein-coding

15-hydroxyprostaglandin dehydrogenase, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

This gene encodes a member of the short-chain nonmetalloenzyme alcohol dehydrogenase protein family. The encoded enzyme is responsible for the metabolism of prostaglandins, which function in a variety of physiologic and cellular processes such as inflammation. Mutations in this gene result in primary autosomal recessive hypertrophic osteoarthropathy and cranioosteoarthropathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

MANE transcript

NM_000860.6

Inheritance

AR, AD

ClinVar variants

P:30U:67B:24

Top phenotype

Hypertrophic osteoarthropathy, primary, autosomal recessive 1

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr4:174,490,175-174,523,154

External References & Databases

Ensembl (ENSG00000164120)

Transcript & Mutation Effects

hg38 • Region Span ~33.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

isolated congenital digital clubbingLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007343

Submitter: Labcorp Genetics (formerly Invitae)

hypertrophic osteoarthropathy, primary, autosomal recessive, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024546

Submitter: Genomics England PanelApp

hypertrophic osteoarthropathy, primary, autosomal recessive, 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024546

Submitter: G2P

pachydermoperiostosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009799

Submitter: Orphanet

cranio-osteoarthropathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015466

Submitter: Orphanet

hypertrophic osteoarthropathy, primary, autosomal recessive, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024546

Submitter: Labcorp Genetics (formerly Invitae)

isolated congenital digital clubbingLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0007343

Submitter: Ambry Genetics

isolated congenital digital clubbingSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007343

Submitter: Orphanet

primary hypertrophic osteoarthropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0016620

Submitter: PanelApp Australia

hypertrophic osteoarthropathy, primary, autosomal recessive, 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024546

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Hypertrophic osteoarthropathy, primary, autosomal recessive 1AR

Manifestation: Musculoskeletal

Intervention: Musculoskeletal

Rationale: Medical treatment (eg, with sulfasalazine, methotrexate) has been described as beneficial related to joint manifestations

Refs: 9402870; 17551338; 17285282; 18500342; 18805827; 19306095; 19568269; 20299379; 20406614; 21426412; 24533558

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HPGD variants in ClinVar

8 Conditions Cataloged

not providedTotal: 103

Hypertrophic osteoarthropathy, primary, autosomal recessive, 1Total: 39

Inborn genetic diseasesTotal: 35

Isolated congenital digital clubbingTotal: 24

HPGD-related disorderTotal: 6

not specifiedTotal: 3

Autosomal recessive primary hypertrophic osteoarthropathyTotal: 2

CranioosteoarthropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000860.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	17 clinvar	3 clinvar	23
missense	2 clinvar	4 clinvar	62 clinvar	3 clinvar	1 clinvar	72
nonsense	3 clinvar	2 clinvar				5
start loss	2 clinvar					2
frameshift	7 clinvar	2 clinvar				9
splice donor/acceptor (+/-2bp)	8 clinvar		2 clinvar			10
Total	22	8	67	20	4	121

Highest pathogenic variant AF is 0.00019764437

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000860.6	RefSeq	NP_000851.2	7	MANE Select
ENST00000296522.11	Ensembl	ENSP00000296522.6	7	MANE Select
NM_001145816.3	RefSeq	NP_001139288.1	6	Standard
NM_001256301.1	RefSeq	NP_001243230.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
Prostaglandin Synthesis and Regulation
Metabolism of lipids
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)
Arachidonic acid metabolism

Biological Process

kidney development
prostaglandin metabolic process
transforming growth factor beta receptor signaling pathway
female pregnancy
parturition

Molecular Function

catalytic activity
prostaglandin E receptor activity
15-hydroxyprostaglandin dehydrogenase (NAD+) activity
protein homodimerization activity
NAD binding

Cellular Component

nucleoplasm
cytoplasm
cytosol
basolateral plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296522
Coding exons: 7
Length: 32978
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 87
Defined: 125748
p: 0.000346

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.119	145	141	1.03	0.00000657	1740
Missense (PolyPhen)		55	56.309	0.97675		646
Synonymous	1.01	41	50.1	0.819	0.00000244	493
Loss of Function	0.930	9	12.6	0.717	5.28e-7	165

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0011	0.0011	notable
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00048	0.00047	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Prostaglandin inactivation. Contributes to the regulation of events that are under the control of prostaglandin levels. Catalyzes the NAD-dependent dehydrogenation of lipoxin A4 to form 15-oxo-lipoxin A4. Inhibits in vivo proliferation of colon cancer cells. {ECO:0000269|PubMed:10837478, ECO:0000269|PubMed:15574495, ECO:0000269|PubMed:16828555}.;
Disease: DISEASE: Hypertrophic osteoarthropathy, primary, autosomal recessive, 1 (PHOAR1) [MIM:259100]: A disease characterized by digital clubbing, periostosis, acroosteolysis, painful joint enlargement, and variable features of pachydermia that include thickened facial skin and a thickened scalp. Other developmental anomalies include delayed closure of the cranial sutures and congenital heart disease. {ECO:0000269|PubMed:18500342}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cranioosteoarthropathy (COA) [MIM:259100]: A form of osteoarthropathy characterized by swelling of the joints, digital clubbing, hyperhidrosis, delayed closure of the fontanels, periostosis, and variable patent ductus arteriosus. Pachydermia is not a prominent feature. {ECO:0000269|PubMed:18500342}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Isolated congenital nail clubbing (ICNC) [MIM:119900]: A rare genodermatosis characterized by enlargement of the nail plate and terminal segments of the fingers and toes, resulting from proliferation of the connective tissues between the nail matrix and the distal phalanx. It is usually symmetrical and bilateral (in some cases unilateral). In nail clubbing usually the distal end of the nail matrix is relatively high compared to the proximal end, while the nail plate is complete but its dimensions and diameter more or less vary in comparison to normal. There may be different fingers and toes involved to varying degrees. Some fingers or toes are spared, but the thumbs are almost always involved. {ECO:0000269|PubMed:18805827}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.232

Intolerance Scores

LoFtool: 0.311
RVIS EVS: -0.21
RVIS percentile EVS: 38.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.164

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium