NPFF

Summary

NPFF (neuropeptide FF-amide peptide precursor, HGNC:7901) is a protein-coding gene on chromosome 12q13.13, encoding Pro-FMRFamide-related neuropeptide FF (O15130). Morphine modulating peptides.

This gene encodes a member of the FMRFamide related peptide (FARP) family of neuropeptides. The encoded preproprotein is proteolytically processed to generate multiple amidated peptides. These peptides may play a role in the regulation of heart rate and blood pressure and the modulation of morphine-induced antinociception. Patients with hypertension exhibit decreased expression of the encoded protein. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed.

Source: NCBI Gene 8620 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_003717

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7901
Approved symbol	NPFF
Name	neuropeptide FF-amide peptide precursor
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	FMRFAL
Ensembl gene	ENSG00000139574
Ensembl biotype	protein_coding
OMIM	604643
Entrez	8620

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000267017, ENST00000448979, ENST00000940394

RefSeq mRNA: 2 — MANE Select: NM_003717 NM_001320296, NM_003717

CCDS: CCDS8862

Canonical transcript exons

ENST00000267017 — 3 exons

Exon	Start	End
ENSE00000938816	53507373	53507484
ENSE00002382266	53506688	53506893
ENSE00003459631	53507021	53507142

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 90.44.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1823 / max 224.5907, expressed in 35 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131248	0.1823	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.44	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.94	gold quality
colonic epithelium	UBERON:0000397	60.93	gold quality
granulocyte	CL:0000094	55.36	gold quality
ganglionic eminence	UBERON:0004023	54.55	gold quality
cortical plate	UBERON:0005343	53.57	gold quality
apex of heart	UBERON:0002098	52.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	49.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	49.04	gold quality
stromal cell of endometrium	CL:0002255	47.74	gold quality
bone marrow cell	CL:0002092	46.38	silver quality
mucosa of transverse colon	UBERON:0004991	46.12	gold quality
duodenum	UBERON:0002114	43.43	gold quality
cerebellum	UBERON:0002037	43.17	gold quality
cerebellar cortex	UBERON:0002129	42.76	gold quality
tonsil	UBERON:0002372	42.26	silver quality
cerebellar hemisphere	UBERON:0002245	42.02	gold quality
ventricular zone	UBERON:0003053	41.66	gold quality
prefrontal cortex	UBERON:0000451	41.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	40.75	gold quality
urinary bladder	UBERON:0001255	40.53	gold quality
hindlimb stylopod muscle	UBERON:0004252	40.38	gold quality
hypothalamus	UBERON:0001898	39.10	gold quality
bone marrow	UBERON:0002371	38.89	silver quality
calcaneal tendon	UBERON:0003701	38.72	silver quality
blood	UBERON:0000178	37.93	gold quality
liver	UBERON:0002107	36.50	gold quality
endocervix	UBERON:0000458	35.71	gold quality
muscle tissue	UBERON:0002385	34.93	gold quality
skeletal muscle tissue	UBERON:0001134	34.89	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-HCAD-38	no	1956.73
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KCNIP3, PDX1, POU1F1, POU2F1

Literature-anchored findings (GeneRIF, showing 7)

• expression of hNPFF2 receptor mRNA was up-regulated by neuropeptide FF (PMID:16336216)
• neuropeptide FF and micro-opioid receptor association could be a possible molecular basis for anti-opioid activity (PMID:17224450)
• the findings from the early studies on the analgesic and morphine modulating activities suggested a role for NPFF in pain modulation–review (PMID:17854890)
• reduction of NPFF release within the dorsal motor nucleus and ambiguus nucleus could serve as a possible cause of the impairment of cardiac vagal control in hypertensive patients (PMID:21120930)
• Our results…highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both migraine with aura and migraine without aura (PMID:26660531)
• The distribution of Neuropeptide FF and Neuropeptide VF in central and peripheral tissues and their role in energy homeostasis control. (PMID:34534716)
• Renal autocrine neuropeptide FF (NPFF) signaling regulates blood pressure. (PMID:38965251)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	npffl	ENSDARG00000045016
mus_musculus	Npff	ENSMUSG00000023052
rattus_norvegicus	Npff	ENSRNOG00000074090

Protein

Protein identifiers

Pro-FMRFamide-related neuropeptide FF — O15130 (reviewed: O15130)

Alternative names: FMRFamide-related peptides

All UniProt accessions (1): O15130

UniProt curated annotations — full annotation on UniProt →

Function. Morphine modulating peptides. Have wide-ranging physiologic effects, including the modulation of morphine-induced analgesia, elevation of arterial blood pressure, and increased somatostatin secretion from the pancreas. Neuropeptide FF potentiates and sensitizes ASIC1 and ASIC3 channels.

Subcellular location. Secreted.

Similarity. Belongs to the FARP (FMRFamide related peptide) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15130-1	1	yes
O15130-2	2

RefSeq proteins (2): NP_001307225, NP_003708* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008065	NPFF	Family

Pfam: PF15085

UniProt features (11 total): peptide 3, propeptide 2, modified residue 2, signal peptide 1, sequence variant 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9JFY	ELECTRON MICROSCOPY	3.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15130-F1	63.92	0.04

Antibody-complex structures (SAbDab): 1 — 9JFY

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 76, 110

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-389397	Orexin and neuropeptides FF and QRFP bind to their respective receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 176 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, MORF_ITGA2, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_REGULATION_OF_BLOOD_PRESSURE, MORF_MSH3, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, GOBP_INSULIN_SECRETION, MORF_BRCA1, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PEPTIDE_SECRETION, GOBP_RESPONSE_TO_FOOD, GOBP_HORMONE_TRANSPORT, GOBP_REGULATION_OF_MEMBRANE_DEPOLARIZATION

GO Biological Process (15): acute inflammatory response to antigenic stimulus (GO:0002438), regulation of membrane depolarization (GO:0003254), positive regulation of cytosolic calcium ion concentration (GO:0007204), neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), response to xenobiotic stimulus (GO:0009410), negative regulation of heart rate (GO:0010459), spinal cord development (GO:0021510), vasopressin secretion (GO:0030103), negative regulation of appetite (GO:0032099), positive regulation of blood pressure (GO:0045777), negative regulation of insulin secretion (GO:0046676), excitatory postsynaptic potential (GO:0060079), maternal process involved in female pregnancy (GO:0060135), somatostatin secretion (GO:0070253)

GO Molecular Function (4): G protein-coupled receptor binding (GO:0001664), signaling receptor binding (GO:0005102), neuropeptide hormone activity (GO:0005184), neuropeptide activity (GO:0160041)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), dendrite (GO:0030425), perikaryon (GO:0043204), axon terminus (GO:0043679), postsynapse (GO:0098794), neuronal dense core vesicle (GO:0098992), vesicle (GO:0031982)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
peptide hormone secretion	2
inflammatory response to antigenic stimulus	1
acute inflammatory response	1
regulation of membrane potential	1
regulation of cellular process	1
membrane depolarization	1
regulation of biological quality	1
G protein-coupled receptor signaling pathway	1
anterograde trans-synaptic signaling	1
response to chemical	1
regulation of heart rate	1
negative regulation of heart contraction	1
central nervous system development	1
anatomical structure development	1
negative regulation of response to food	1
regulation of appetite	1
regulation of blood pressure	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
female pregnancy	1
multicellular organismal reproductive process	1
signaling receptor binding	1
protein binding	1
hormone activity	1
neuropeptide activity	1
receptor ligand activity	1
neuropeptide receptor binding	1
neuron projection	1
dendritic tree	1
neuronal cell body	1
neuron projection terminus	1
presynapse	1
distal axon	1
synapse	1
dense core granule	1

Protein interactions and networks

STRING

456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPFF	NPFFR2	Q9Y5X5	998
NPFF	NPFFR1	Q9GZQ6	995
NPFF	MAS1	P04201	961
NPFF	PRLH	P81277	941
NPFF	PRLHR	P49683	870
NPFF	MRGPRD	Q8TDS7	864
NPFF	MRGPRX2	Q96LB1	852
NPFF	MRGPRX3	Q96LB0	851
NPFF	MRGPRX1	Q96LB2	836
NPFF	NPVF	Q9HCQ7	835
NPFF	MAS1L	P35410	822
NPFF	MRGPRF	Q96AM1	822
NPFF	MRGPRX4	Q96LA9	822
NPFF	QRFP	P83859	778
NPFF	KISS1	Q15726	768

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ZDHHC17	NPFF	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (2): NPFF (Two-hybrid), NPFF (Affinity Capture-MS)

ESM2 similar proteins: D3Z752, M0R8L2, O00230, O15130, O57312, O62827, O77559, O93464, P01143, P01169, P01258, P01297, P08435, P08949, P08989, P10093, P12760, P24393, P35318, P47851, P49188, P53366, P55089, P55090, P55099, P63152, P63153, P81277, P81278, P81615, P81872, P83859, P83860, P83862, Q13519, Q2T9U8, Q6ECK6, Q800I8, Q863C3, Q86UU9

Diamond homologs: O15130, P15506, Q9TUX7, Q9WVA8, Q9WVA9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NPFF	up-regulates	NPFFR1	binding
NPFF	up-regulates	NPFFR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

356 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53507020:CCT:C	donor_gain	0.9600
12:53507017:TCA:T	donor_loss	0.9500
12:53507018:CA:C	donor_loss	0.9500
12:53507019:A:AC	donor_gain	0.9500
12:53507020:C:CC	donor_gain	0.9500
12:53507149:C:CT	acceptor_gain	0.9300
12:53507160:C:CT	acceptor_gain	0.9100
12:53507138:TCCTC:T	acceptor_loss	0.9000
12:53507139:CCTCC:C	acceptor_loss	0.9000
12:53507141:TC:T	acceptor_loss	0.9000
12:53507143:C:CA	acceptor_loss	0.9000
12:53507144:T:A	acceptor_loss	0.9000
12:53507150:A:T	acceptor_gain	0.9000
12:53507372:CCG:C	donor_gain	0.8900
12:53506891:AACC:A	acceptor_loss	0.8700
12:53507161:A:T	acceptor_gain	0.8700
12:53506895:T:G	acceptor_loss	0.8600
12:53506898:GGAAA:G	acceptor_loss	0.8400
12:53506899:GAAAG:G	acceptor_loss	0.8400
12:53506900:AAAGA:A	acceptor_loss	0.8400
12:53506901:AAGAT:A	acceptor_loss	0.8300
12:53507019:ACCT:A	donor_gain	0.8100
12:53507020:CCTC:C	donor_gain	0.8100
12:53506896:TAGGA:T	acceptor_loss	0.8000
12:53506897:AGGAA:A	acceptor_loss	0.8000
12:53507019:AC:A	donor_gain	0.8000
12:53507020:CC:C	donor_gain	0.8000
12:53507020:CCTCT:C	donor_gain	0.7900
12:53507371:A:AC	donor_gain	0.7900
12:53507372:C:CC	donor_gain	0.7900

AlphaMissense

723 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53506788:A:C	F110L	0.987
12:53506788:A:T	F110L	0.987
12:53506790:A:G	F110L	0.987
12:53506890:A:C	F76L	0.981
12:53506890:A:T	F76L	0.981
12:53506892:A:G	F76L	0.981
12:53506789:A:C	F110C	0.959
12:53506794:T:A	Q108H	0.949
12:53506794:T:G	Q108H	0.949
12:53506891:A:C	F76C	0.937
12:53506793:G:T	R109S	0.929
12:53506786:C:T	G111E	0.928
12:53506786:C:A	G111V	0.925
12:53507023:C:A	Q74H	0.921
12:53507023:C:G	Q74H	0.921
12:53506804:G:T	A105D	0.907
12:53506782:C:A	K112N	0.906
12:53506782:C:G	K112N	0.906
12:53506893:C:A	R75S	0.900
12:53506893:C:G	R75S	0.900
12:53506790:A:T	F110I	0.898
12:53506815:G:C	F101L	0.889
12:53506815:G:T	F101L	0.889
12:53506817:A:G	F101L	0.889
12:53506787:C:A	G111W	0.887
12:53506779:C:A	K113N	0.886
12:53506779:C:G	K113N	0.886
12:53506790:A:C	F110V	0.885
12:53506789:A:G	F110S	0.883
12:53507038:G:C	F69L	0.880

dbSNP variants (sampled 300 via entrez): RS1000102741 (12:53506644 G>A), RS1001018949 (12:53509159 C>T), RS1005092602 (12:53506512 C>G), RS1006466788 (12:53507317 A>C), RS1008898742 (12:53509186 A>G), RS1009562140 (12:53509148 G>A), RS1009612841 (12:53508810 AGG>A), RS1010983582 (12:53506572 G>A,C), RS1011898703 (12:53506562 C>G,T), RS1012605150 (12:53507657 C>A,T), RS1012655900 (12:53507998 G>T), RS1014892678 (12:53507590 A>C,G), RS1015507880 (12:53507959 G>A), RS1015897163 (12:53506190 C>T), RS1016242575 (12:53508474 C>G,T)

Disease associations

OMIM: gene MIM:604643 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005956_70	Waist-to-hip ratio adjusted for BMI	4.000000e-13
GCST005957_6	Waist-to-hip ratio adjusted for BMI (age <50)	6.000000e-06
GCST005958_9	Waist-to-hip ratio adjusted for BMI (age >50)	1.000000e-08
GCST005962_20	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Particulate Matter	decreases expression	1

Clinical trials (associated diseases)

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