PIGF

Summary

PIGF (phosphatidylinositol glycan anchor biosynthesis class F, HGNC:8962) is a protein-coding gene on chromosome 2p21, encoding GPI ethanolamine phosphate transferase, stabilizing subunit (Q07326). Stabilizing subunit of the ethanolamine phosphate transferase 3 and ethanolamine phosphate transferase 2 complexes that sequentially transfer an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose and the….

This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 5281 — RefSeq curated summary.

At a glance

• Gene–disease (curated): onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (Limited, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 57 total
• Phenotypes (HPO): 29
• MANE Select transcript: NM_002643

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8962
Approved symbol	PIGF
Name	phosphatidylinositol glycan anchor biosynthesis class F
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	PIG-F
Ensembl gene	ENSG00000151665
Ensembl biotype	protein_coding
OMIM	600153
Entrez	5281

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000281382, ENST00000306465, ENST00000412717, ENST00000420164, ENST00000474980, ENST00000482786, ENST00000495933, ENST00000903157, ENST00000903158, ENST00000903159, ENST00000923044, ENST00000923047

RefSeq mRNA: 2 — MANE Select: NM_002643 NM_002643, NM_173074

CCDS: CCDS1827, CCDS1828

Canonical transcript exons

ENST00000281382 — 6 exons

Exon	Start	End
ENSE00001000980	46613694	46613785
ENSE00001169649	46616970	46617041
ENSE00001340000	46614937	46615185
ENSE00001669051	46580937	46581591
ENSE00003482085	46592475	46592583
ENSE00003503199	46612228	46612344

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 94.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.1790 / max 409.9086, expressed in 1801 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28191	27.7140	1798
28190	1.1076	653
28192	0.3201	140
28193	0.0373	13

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	94.66	gold quality
islet of Langerhans	UBERON:0000006	93.43	gold quality
right adrenal gland	UBERON:0001233	93.22	gold quality
rectum	UBERON:0001052	93.20	gold quality
right adrenal gland cortex	UBERON:0035827	93.19	gold quality
adrenal tissue	UBERON:0018303	92.89	gold quality
left adrenal gland	UBERON:0001234	92.79	gold quality
left adrenal gland cortex	UBERON:0035825	92.57	gold quality
mucosa of transverse colon	UBERON:0004991	92.41	gold quality
monocyte	CL:0000576	92.36	gold quality
stromal cell of endometrium	CL:0002255	92.19	gold quality
ventricular zone	UBERON:0003053	92.19	gold quality
body of pancreas	UBERON:0001150	92.10	gold quality
calcaneal tendon	UBERON:0003701	92.05	gold quality
mononuclear cell	CL:0000842	91.98	gold quality
leukocyte	CL:0000738	91.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.67	gold quality
adrenal gland	UBERON:0002369	91.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.38	gold quality
right testis	UBERON:0004534	91.35	gold quality
gall bladder	UBERON:0002110	91.19	gold quality
left testis	UBERON:0004533	91.11	gold quality
adrenal cortex	UBERON:0001235	90.92	gold quality
omental fat pad	UBERON:0010414	90.76	gold quality
peritoneum	UBERON:0002358	90.71	gold quality
testis	UBERON:0000473	90.66	gold quality
pancreas	UBERON:0001264	90.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.24	gold quality
ganglionic eminence	UBERON:0004023	90.14	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.11	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

34 targeting PIGF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-1537-5P	98.70	68.33	999
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-495-5P	97.62	68.28	682
HSA-MIR-4287	97.55	67.24	1247
HSA-MIR-4685-3P	97.55	67.35	1255
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-643	97.35	67.91	805
HSA-MIR-4726-5P	97.24	65.67	1299

Literature-anchored findings (GeneRIF, showing 4)

• mechanism for the regulation of glycosylphosphatidylinositols synthesis (PMID:15632136)
• PIGF gene is upregulated in patients diagnosed with retinal reactive astrocytic tumors. (PMID:24921169)
• A highly conserved motif in PIGF is not involved in binding to PIGO or PIGG, but critical for its function. (PMID:25074286)
• PIGF deficiency causes a phenotype overlapping with DOORS syndrome. (PMID:33386993)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pigf	ENSDARG00000032780
mus_musculus	Pigf	ENSMUSG00000024145
rattus_norvegicus	Pigf	ENSRNOG00000015325
drosophila_melanogaster	PIG-F	FBGN0036893
caenorhabditis_elegans		WBGENE00302976

Protein

Protein identifiers

GPI ethanolamine phosphate transferase, stabilizing subunit — Q07326 (reviewed: Q07326)

Alternative names: GPI ethanolamine phosphate transferase 2, stabilizing subunit, GPI ethanolamine phosphate transferase 3, stabilizing subunit, GPI11 homolog, Phosphatidylinositol-glycan biosynthesis class F protein

All UniProt accessions (5): Q07326, E5RIN5, F8WEN5, H7C392, Q6IB04

UniProt curated annotations — full annotation on UniProt →

Function. Stabilizing subunit of the ethanolamine phosphate transferase 3 and ethanolamine phosphate transferase 2 complexes that sequentially transfer an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose and the second alpha-1,6-linked mannose of a 2-acyl-6-[alpha-D-mannosyl-(1->2)-alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H6) intermediate to generate a 2-acyl-6-[6-phosphoethanolamine-alpha-D-mannosyl-(1->2)-6-phosphoethanolamine-alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl]-1-(1-radyl,2-acyl-sn-glycero-3-phospho)-1D-myo-inositol (also termed H8). Participates in the tenth and eleventh steps of the glycosylphosphatidylinositol-anchor biosynthesis, in association with PIGO and PIGG, respectively.

Subunit / interactions. Part of the ethanolamine phosphate transferase 3 complex composed by PIGO and PIGF. Part of the ethanolamine phosphate transferase 2 complex with PIGG. PIGF is required to stabilize PIGG and PIGO.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS) [MIM:619356] An autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, seizures or tonic posturing, dysmorphic facial features, and hypoplastic terminal phalanges and nails. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor biosynthesis.

Similarity. Belongs to the PIGF family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q07326-1	1	yes
Q07326-2	2

RefSeq proteins (2): NP_002634, NP_775097 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009580	GPI_biosynthesis_protein_Pig-F	Family

Pfam: PF06699

UniProt features (9 total): transmembrane region 6, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07326-F1	92.60	0.82

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-162710	Synthesis of glycosylphosphatidylinositol (GPI)

MSigDB gene sets: 247 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MORF_MSH3, GOBP_GLYCOLIPID_BIOSYNTHETIC_PROCESS, REACTOME_SYNTHESIS_OF_GLYCOSYLPHOSPHATIDYLINOSITOL_GPI, MORF_BRCA1, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS

GO Biological Process (1): GPI anchor biosynthetic process (GO:0006506)

GO Molecular Function (2): ethanolaminephosphotransferase activity (GO:0004307), protein binding (GO:0005515)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational modification: synthesis of GPI-anchored proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GPI anchor metabolic process	1
glycolipid biosynthetic process	1
glycerophospholipid biosynthetic process	1
GPI anchored protein biosynthesis	1
CDP-alcohol phosphatidyltransferase activity	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIGF	PIGA	P37287	849
PIGF	TMEM247	A6NEH6	560
PIGF	FLT1	P16057	506
PIGF	ATP6V1E2	Q96A05	461
PIGF	PIGN	O95427	460
PIGF	ALG11	Q2TAA5	443
PIGF	DPM2	O94777	442
PIGF	ALG13	Q9NP73	432
PIGF	CDKN2A	P42771	427
PIGF	OST4	P0C6T2	420
PIGF	CHSY1	Q86X52	412
PIGF	ACTRT2	Q8TDY3	406
PIGF	RHOQ	P17081	392
PIGF	ZFAND2A	Q8N6M9	387
PIGF	HIF1A	Q16665	384

IntAct

26 interactions, top by confidence:

A	B	Type	Score
PIGF	LYVE1	psi-mi:“MI:0915”(physical association)	0.560
PIGF	TIMMDC1	psi-mi:“MI:0915”(physical association)	0.560
PIGF	TMEM130	psi-mi:“MI:0915”(physical association)	0.560
PIGF	MANBAL	psi-mi:“MI:0915”(physical association)	0.560
PIGF	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
PIGF	GPR152	psi-mi:“MI:0915”(physical association)	0.560
PIGF	AQP6	psi-mi:“MI:0915”(physical association)	0.560
PIGF	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
PIGF	SUPT5H	psi-mi:“MI:0914”(association)	0.350
MANBAL	PIGF	psi-mi:“MI:0915”(physical association)	0.000
PIGF	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000
PIGF	GPR152	psi-mi:“MI:0915”(physical association)	0.000
PIGF	AQP6	psi-mi:“MI:0915”(physical association)	0.000
PIGF	TMEM86B	psi-mi:“MI:0915”(physical association)	0.000
PIGF	MANBAL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): PIGF (Synthetic Lethality), PIGF (Two-hybrid), PIGF (Two-hybrid), PIGF (Two-hybrid), PIGF (Two-hybrid), PIGF (Two-hybrid), TMEM130 (Two-hybrid), GPR152 (Two-hybrid), TMEM86B (Two-hybrid), CCNL2 (Affinity Capture-MS), HDAC6 (Affinity Capture-MS), AKAP9 (Affinity Capture-MS), UBE3A (Affinity Capture-MS), PARN (Affinity Capture-MS), SUPT6H (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3MKU8, A1L3G9, A9RA88, B0CMA4, E7FE40, G5EBX4, I6VSD2, O09101, O45876, O59802, O64761, Q06636, Q07326, Q1LZA4, Q28FG4, Q2TA63, Q3SZR6, Q3UUQ7, Q49LR9, Q5F3W2, Q5GH70, Q5R687, Q5U4Q2, Q641M3, Q66J01, Q66J27, Q6BHK4, Q6C741, Q6CTT3, Q6FSD1, Q6PQZ3, Q75EY7, Q75T13, Q765A7, Q7TSN4, Q7Z7B1, Q80UA9, Q8BI36, Q8C2L6, Q8C398

Diamond homologs: O09101, P0C148, Q07326, Q4HXT5, Q4WIQ0, Q5AFT2, Q6BHK4, Q6C741, Q6CTT3, Q6FSD1, Q75EY7, Q871U9, Q9Y7P2, Q06636, F1QWW8, P0CR36, P0CR37, Q06136, Q2KIJ5, Q4WSZ0, Q556J2, Q5BE65, Q6CE86, Q6GV12, Q9RPT1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PIGF	“up-regulates quantity by stabilization”	PIGG	binding
PIGF	“down-regulates quantity by destabilization”	PIGO

Disease & clinical

Clinical variants and AI predictions

ClinVar

57 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:46592535:G:C	S162R	0.994
2:46592535:G:T	S162R	0.994
2:46592537:T:G	S162R	0.994
2:46592480:A:G	W181R	0.989
2:46592480:A:T	W181R	0.989
2:46581588:A:G	W184R	0.986
2:46581588:A:T	W184R	0.986
2:46592478:C:A	W181C	0.981
2:46592478:C:G	W181C	0.981
2:46581586:C:A	W184C	0.980
2:46581586:C:G	W184C	0.980
2:46592490:C:A	W177C	0.979
2:46592490:C:G	W177C	0.979
2:46592522:A:G	W167R	0.979
2:46592522:A:T	W167R	0.979
2:46581554:C:T	G195D	0.978
2:46581585:G:A	P185S	0.970
2:46581543:C:G	G199R	0.969
2:46581584:G:T	P185H	0.968
2:46592492:A:G	W177R	0.968
2:46592492:A:T	W177R	0.968
2:46581542:C:T	G199D	0.967
2:46592475:C:A	Q182H	0.967
2:46592475:C:G	Q182H	0.967
2:46612318:G:T	A116E	0.967
2:46612253:A:G	W138R	0.962
2:46612253:A:T	W138R	0.962
2:46581576:A:G	C188R	0.952
2:46581585:G:T	P185T	0.952
2:46615038:A:G	W43R	0.952

dbSNP variants (sampled 300 via entrez): RS1000004024 (2:46599376 A>T), RS1000079284 (2:46613295 A>C), RS1000141548 (2:46605176 T>C), RS1000196888 (2:46610197 A>G), RS1000273547 (2:46597459 C>T), RS1000331085 (2:46597261 C>T), RS1000491867 (2:46602686 T>A), RS1000508122 (2:46593108 G>T), RS1000513507 (2:46605411 T>A), RS1000536083 (2:46586762 C>G), RS1000589820 (2:46587081 C>A,T), RS1000601374 (2:46608853 TC>T), RS1000839661 (2:46619008 A>G), RS1000844119 (2:46603022 T>A,C), RS1000896622 (2:46615330 G>A,C)

Disease associations

OMIM: gene MIM:600153 | disease phenotypes: MIM:619356

GenCC curated gene-disease

Disease	Classification	Inheritance
onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome	Limited	AR

Mondo (1): onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (MONDO:0859161)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000347	Micrognathia
HP:0000463	Anteverted nares
HP:0000691	Microdontia
HP:0000696	Delayed eruption of permanent teeth
HP:0000826	Precocious puberty
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001631	Atrial septal defect
HP:0001800	Hypoplastic toenails
HP:0001804	Hypoplastic fingernail
HP:0001857	Short distal phalanx of toe
HP:0002069	Bilateral tonic-clonic seizure
HP:0002421	Poor head control
HP:0003196	Short nose
HP:0003577	Congenital onset
HP:0004379	Abnormality of alkaline phosphatase level
HP:0005707	Bilateral triphalangeal thumbs
HP:0008398	Hypoplastic fifth fingernail
HP:0009882	Short distal phalanx of finger
HP:0010864	Severe intellectual disability
HP:0012168	Head-banging
HP:0012553	Hypoplastic thumbnail
HP:0031061	Impaired toileting ability
HP:0200105	Absent fifth toenail

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000839_4	Height	3.000000e-07
GCST010697_51	Cortical surface area (min-P)	4.000000e-12
GCST010698_64	Subcortical volume (min-P)	3.000000e-09
GCST010699_93	Brain morphology (min-P)	1.000000e-12
GCST010700_22	Cortical thickness (MOSTest)	9.000000e-11
GCST010701_108	Cortical surface area (MOSTest)	4.000000e-12
GCST010702_134	Subcortical volume (MOSTest)	2.000000e-14
GCST010703_146	Brain morphology (MOSTest)	5.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression	3
potassium chromate(VI)	decreases expression, affects cotreatment	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression, affects cotreatment	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
chromium hexavalent ion	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression, affects cotreatment	1
MT19c compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Gold	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Nicotine	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Dihydrotestosterone	increases expression	1
Thiram	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.