NXPH1

Summary

NXPH1 (neurexophilin 1, HGNC:20693) is a protein-coding gene on chromosome 7p21.3, encoding Neurexophilin-1 (P58417). May be signaling molecules that resemble neuropeptides and that act by binding to alpha-neurexins and possibly other receptors.

This gene is a member of the neurexophilin family and encodes a secreted protein with a variable N-terminal domain, a highly conserved, N-glycosylated central domain, a short linker region, and a cysteine-rich C-terminal domain. This protein forms a very tight complex with alpha neurexins, a group of proteins that promote adhesion between dendrites and axons.

Source: NCBI Gene 30010 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_152745

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20693
Approved symbol	NXPH1
Name	neurexophilin 1
Location	7p21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000122584
Ensembl biotype	protein_coding
OMIM	604639
Entrez	30010

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000405863, ENST00000429542, ENST00000438764, ENST00000497400, ENST00000602349

RefSeq mRNA: 1 — MANE Select: NM_152745 NM_152745

CCDS: CCDS47540

Canonical transcript exons

ENST00000405863 — 3 exons

Exon	Start	End
ENSE00001553709	8433609	8434755
ENSE00001559531	8751008	8752961
ENSE00003530743	8435604	8435767

Expression profiles

Bgee: expression breadth broad, 95 present calls, max score 90.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9694 / max 132.1536, expressed in 132 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77225	0.3254	98
77229	0.1317	68
77230	0.1262	66
77228	0.0805	65
77231	0.0665	26
77234	0.0499	25
77227	0.0406	26
77233	0.0381	21
77223	0.0359	24
77224	0.0357	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	90.59	gold quality
endothelial cell	CL:0000115	90.58	gold quality
right adrenal gland	UBERON:0001233	89.11	gold quality
secondary oocyte	CL:0000655	88.28	gold quality
prefrontal cortex	UBERON:0000451	88.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.08	gold quality
left adrenal gland	UBERON:0001234	87.94	gold quality
left adrenal gland cortex	UBERON:0035825	87.88	gold quality
adrenal cortex	UBERON:0001235	87.61	gold quality
hypothalamus	UBERON:0001898	87.48	gold quality
anterior cingulate cortex	UBERON:0009835	87.19	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.83	gold quality
amygdala	UBERON:0001876	84.55	gold quality
adrenal gland	UBERON:0002369	84.55	gold quality
neocortex	UBERON:0001950	83.66	gold quality
frontal cortex	UBERON:0001870	83.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.51	gold quality
cerebral cortex	UBERON:0000956	82.24	gold quality
cortical plate	UBERON:0005343	82.10	gold quality
caudate nucleus	UBERON:0001873	81.98	gold quality
temporal lobe	UBERON:0001871	80.43	gold quality
right frontal lobe	UBERON:0002810	80.01	gold quality
forebrain	UBERON:0001890	79.11	gold quality
primary visual cortex	UBERON:0002436	79.04	gold quality
putamen	UBERON:0001874	78.85	gold quality
nucleus accumbens	UBERON:0001882	78.78	gold quality
superior vestibular nucleus	UBERON:0007227	78.74	gold quality
Ammon’s horn	UBERON:0001954	78.08	gold quality
brain	UBERON:0000955	77.90	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	2184.32
E-HCAD-35	yes	2116.27
E-GEOD-93593	yes	1565.42
E-HCAD-25	yes	1519.00
E-MTAB-8894	yes	712.75
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

130 targeting NXPH1, 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-4673	100.00	66.64	1490
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-15A-5P	99.90	72.80	2787

Literature-anchored findings (GeneRIF, showing 11)

• In rat, the secreted ligand for alpha-neurexin, neurexophilin 1, is expressed in the postnatal olfactory bulb. (PMID:12141453)
• results demonstrate the presence and function of a regulated signaling axis in hematopoiesis centered on NRXN1alpha and its modulation by DAG1 and NXPH1 (PMID:21628410)
• Data indicate taht candidate genes ACTB, BZW, OCM, MACC1, NXPH1, PRPS1L1, RAC1 and RPA3, which lie within the DFNB90 region, were sequenced and no potentially causal variants were identified. (PMID:21734401)
• Data indicate that median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were >/=30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. (PMID:22930747)
• Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with diarrhoea and constipation predominant irritable bowel syndrome, respectively, in two independent cohorts. (PMID:24041540)
• The role of NXPH1 in in paranoid schizophrenia development in Russians. (PMID:26410934)
• identification of SNPs within the IQCJ, NXPH1, PHF17 and MYB genes partly explaining the large interindividual variability observed in plasma triglyceride levels in response to an n-3 fatty acid supplementation (PMID:27160456)
• expression inversely correlated with N stage in pancreatic ductal adenocarcinoma (PMID:27817196)
• A genome-wide association study (GWAS) identified loci associated with the plasma triglyceride (TG) response to omega-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. (PMID:28134766)
• miR-194-5p inhibits LPS-induced astrocytes activation by directly targeting neurexophilin 1. (PMID:32533463)
• In rat, neurexophilin 1 forms a very tight complex with neurexin I alpha. (PMID:8699246)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nxph1	ENSDARG00000033447
mus_musculus	Nxph1	ENSMUSG00000046178
rattus_norvegicus	Nxph1	ENSRNOG00000008939

Paralogs (3): NXPH2 (ENSG00000144227), NXPH4 (ENSG00000182379), NXPH3 (ENSG00000182575)

Protein

Protein identifiers

Neurexophilin-1 — P58417 (reviewed: P58417)

All UniProt accessions (5): C9JE46, C9JPD0, P58417, Q3LID8, R4GMM9

UniProt curated annotations — full annotation on UniProt →

Function. May be signaling molecules that resemble neuropeptides and that act by binding to alpha-neurexins and possibly other receptors.

Subcellular location. Secreted.

Similarity. Belongs to the neurexophilin family.

RefSeq proteins (1): NP_689958* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010450	Nxph	Family
IPR026845	NXPH/NXPE	Family

Pfam: PF06312

UniProt features (13 total): glycosylation site 6, region of interest 4, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58417-F1	67.14	0.32

Functional residue map

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

Glycosylation sites (6): 156, 162, 23, 68, 93, 146

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GGGTGGRR_PAX4_03, USF_C, GOBP_CELL_CELL_SIGNALING, CATRRAGC_UNKNOWN, CATTTCA_MIR203, AAAGACA_MIR511, OCT1_07, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, ATTCTTT_MIR186, TGACATY_UNKNOWN, HIF1_Q3, GOBP_SYNAPTIC_SIGNALING, AACTTT_UNKNOWN, TGGNNNNNNKCCAR_UNKNOWN

GO Biological Process (1): modulation of chemical synaptic transmission (GO:0050804)

GO Molecular Function (1): signaling receptor binding (GO:0005102)

GO Cellular Component (4): synaptic cleft (GO:0043083), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
synapse	2
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
protein binding	1
extracellular region	1

Protein interactions and networks

STRING

1903 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NXPH1	NRXN1	Q9ULB1	937
NXPH1	NRXN2	Q9P2S2	608
NXPH1	LRRTM1	Q86UE6	473
NXPH1	TTC13	Q8NBP0	470
NXPH1	NLGN1	Q8N2Q7	467
NXPH1	LRRTM3	Q86VH5	458
NXPH1	APBA1	Q02410	456
NXPH1	GAD2	Q05329	442
NXPH1	IQCJ	Q1A5X6	414
NXPH1	GRM5	P41594	406
NXPH1	GABRB1	P18505	398
NXPH1	APOF	Q13790	391
NXPH1	SYNPR	Q8TBG9	387
NXPH1	ELAVL4	P26378	379
NXPH1	ECEL1	O95672	373

IntAct

5 interactions, top by confidence:

A	B	Type	Score
NXPH1	RAD51C	psi-mi:“MI:0914”(association)	0.350
NXPH1	PTPRK	psi-mi:“MI:0914”(association)	0.350
NXPH1	ADAM10	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): PYCRL (Affinity Capture-MS), KIAA0319L (Affinity Capture-MS), UBE3D (Affinity Capture-MS), RNASEL (Affinity Capture-MS), CNTNAP3 (Affinity Capture-MS), SP3 (Affinity Capture-MS), RAD51C (Affinity Capture-MS), YTHDC2 (Affinity Capture-MS), CSPG4 (Affinity Capture-MS), PTPRK (Affinity Capture-MS), OS9 (Affinity Capture-MS), PRPS1L1 (Affinity Capture-MS), RHOT2 (Affinity Capture-MS), CTHRC1 (Affinity Capture-MS), HLA-DQB1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A1XQX1, D4A1J9, O00451, O08842, O08957, O13097, O13156, O13157, O42596, O95156, O95980, P01346, P09535, P0DJQ9, P52795, P52796, P56159, P58417, P83094, P97785, P98172, Q0PMD2, Q17QD6, Q28143, Q28145, Q5E9X0, Q5R530, Q5RAD6, Q61200, Q62997, Q6NW40, Q6PCX7, Q6PFE7, Q7TQ33, Q80YA9, Q8BXA0, Q8C985, Q8CFV4, Q8IYR6

Diamond homologs: O95156, O95157, O95158, P58417, Q28145, Q5E9M6, Q5R530, Q61199, Q61200, Q63366, Q8WMI6, Q8WMJ4, Q8WMJ7, Q91VX5, Q9Z2N4, Q9Z2N5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NXPH1	up-regulates	NRXN3	binding
NXPH1	up-regulates	NRXN1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2953 predictions. Top by Δscore:

Variant	Effect	Δscore
7:8434751:GTGCG:G	donor_gain	1.0000
7:8750999:T:A	acceptor_gain	1.0000
7:8751003:TTCA:T	acceptor_loss	1.0000
7:8751006:A:AG	acceptor_gain	1.0000
7:8751007:G:GG	acceptor_gain	1.0000
7:8751007:GGT:G	acceptor_gain	1.0000
7:8751007:GGTC:G	acceptor_gain	1.0000
7:8751007:GGTCA:G	acceptor_gain	1.0000
7:8434753:GCG:G	donor_gain	0.9900
7:8434756:G:GG	donor_gain	0.9900
7:8434757:T:G	donor_loss	0.9900
7:8475971:G:GT	donor_gain	0.9900
7:8549120:C:CA	acceptor_gain	0.9900
7:8549121:G:A	acceptor_gain	0.9900
7:8549128:A:G	acceptor_gain	0.9900
7:8593274:G:GT	donor_gain	0.9900
7:8675477:A:G	acceptor_gain	0.9900
7:8675478:G:GG	acceptor_gain	0.9900
7:8751006:AG:A	acceptor_gain	0.9900
7:8751007:G:A	acceptor_gain	0.9900
7:8434752:TGCG:T	donor_gain	0.9800
7:8434753:GCGG:G	donor_gain	0.9800
7:8434754:CG:C	donor_gain	0.9800
7:8434755:GG:G	donor_gain	0.9800
7:8435768:G:GG	donor_gain	0.9800
7:8519541:A:T	donor_gain	0.9800
7:8675476:A:G	acceptor_gain	0.9800
7:8690239:TAGTA:T	acceptor_gain	0.9800
7:8435694:G:GT	donor_gain	0.9700
7:8435765:TTGG:T	donor_loss	0.9700

AlphaMissense

1790 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:8751301:G:C	K116N	1.000
7:8751301:G:T	K116N	1.000
7:8751303:A:T	K117I	1.000
7:8751304:A:C	K117N	1.000
7:8751304:A:T	K117N	1.000
7:8751308:T:A	F119I	1.000
7:8751308:T:C	F119L	1.000
7:8751309:T:C	F119S	1.000
7:8751309:T:G	F119C	1.000
7:8751310:T:A	F119L	1.000
7:8751310:T:G	F119L	1.000
7:8751311:G:A	G120R	1.000
7:8751311:G:C	G120R	1.000
7:8751312:G:A	G120E	1.000
7:8751314:T:A	W121R	1.000
7:8751314:T:C	W121R	1.000
7:8751315:G:C	W121S	1.000
7:8751316:G:C	W121C	1.000
7:8751316:G:T	W121C	1.000
7:8751317:G:A	G122S	1.000
7:8751317:G:C	G122R	1.000
7:8751317:G:T	G122C	1.000
7:8751318:G:A	G122D	1.000
7:8751318:G:T	G122V	1.000
7:8751323:T:C	F124L	1.000
7:8751324:T:C	F124S	1.000
7:8751324:T:G	F124C	1.000
7:8751325:T:A	F124L	1.000
7:8751325:T:G	F124L	1.000
7:8751329:T:C	S126P	1.000

dbSNP variants (sampled 300 via entrez): RS1000005918 (7:8485563 G>A), RS1000030661 (7:8528707 A>C,G), RS1000041039 (7:8732808 T>C), RS1000045808 (7:8472309 C>A,T), RS1000057748 (7:8723438 A>C), RS1000069969 (7:8737019 C>G,T), RS1000081839 (7:8712252 T>C), RS1000104061 (7:8706799 G>A,C), RS1000105024 (7:8459871 T>C), RS1000108821 (7:8689633 G>A), RS1000115545 (7:8575443 A>G), RS1000130075 (7:8622784 A>G), RS1000132567 (7:8731342 A>G,T), RS1000143837 (7:8491788 A>G), RS1000145163 (7:8699524 C>T)

Disease associations

OMIM: gene MIM:604639 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000189_41	Protein quantitative trait loci	1.000000e-06
GCST000226_2	Neuroticism	7.000000e-06
GCST000573_12	Brain imaging	1.000000e-06
GCST000573_6	Brain imaging	1.000000e-06
GCST001632_2	Response to fenofibrate	1.000000e-06
GCST001632_7	Response to fenofibrate	7.000000e-06
GCST001762_239	Obesity-related traits	7.000000e-06
GCST001762_598	Obesity-related traits	8.000000e-06
GCST001762_648	Obesity-related traits	8.000000e-06
GCST003564_7	Waist-to-hip ratio adjusted for body mass index	7.000000e-06
GCST004029_20	Angiotensin-converting enzyme inhibitor intolerance	9.000000e-06
GCST005588_32	Idiopathic dilated cardiomyopathy	6.000000e-06
GCST006055_5	Response to long-chain n-3 polyunsaturated fatty acid supplementation (change in triglyceride levels)	3.000000e-06
GCST008892_12	Working memory	8.000000e-06
GCST009391_962	Metabolite levels	8.000000e-06
GCST012490_147	Femur bone mineral density x serum urate levels interaction	5.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0003939	energy intake
EFO:0004501	HOMA-IR
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0007681	triglyceride change measurement
EFO:0004335	short-term memory
EFO:0010444	triacylglycerol 60:12 measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Carbamazepine	affects expression	1
Catechin	affects cotreatment, decreases expression	1
Folic Acid	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Niclosamide	decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Serpentine	increases methylation	1
Asbestos, Crocidolite	increases methylation	1

Clinical trials (associated diseases)

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