NNAT

Summary

NNAT (neuronatin, HGNC:7860) is a protein-coding gene on chromosome 20q11.23, encoding Neuronatin (Q16517). May participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system.

The protein encoded by this gene is a proteolipid that may be involved in the regulation of ion channels during brain development. The encoded protein may also play a role in forming and maintaining the structure of the nervous system. This gene is found within an intron of another gene, bladder cancer associated protein, but on the opposite strand. This gene is imprinted and is expressed only from the paternal allele.

Source: NCBI Gene 4826 — RefSeq curated summary.

At a glance

• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005386

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7860
Approved symbol	NNAT
Name	neuronatin
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	Peg5
Ensembl gene	ENSG00000053438
Ensembl biotype	protein_coding
OMIM	603106
Entrez	4826

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000346199, ENST00000647955, ENST00000649309, ENST00000649451, ENST00000649697

RefSeq mRNA: 3 — MANE Select: NM_005386 NM_001322802, NM_005386, NM_181689

CCDS: CCDS13296, CCDS13297, CCDS93038

Canonical transcript exons

ENST00000649451 — 3 exons

Exon	Start	End
ENSE00000661891	37522358	37522438
ENSE00001334893	37522667	37523690
ENSE00003834281	37521250	37521403

Expression profiles

Bgee: expression breadth ubiquitous, 244 present calls, max score 99.75.

FANTOM5 (CAGE): breadth broad, TPM avg 57.5057 / max 6325.5774, expressed in 590 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184501	57.2643	590
184502	0.2413	116

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.75	gold quality
ganglionic eminence	UBERON:0004023	99.75	gold quality
cortical plate	UBERON:0005343	99.63	gold quality
pituitary gland	UBERON:0000007	99.49	gold quality
adenohypophysis	UBERON:0002196	99.45	gold quality
nucleus accumbens	UBERON:0001882	99.22	gold quality
embryo	UBERON:0000922	99.04	gold quality
caudate nucleus	UBERON:0001873	98.33	gold quality
amygdala	UBERON:0001876	97.71	gold quality
putamen	UBERON:0001874	97.63	gold quality
prefrontal cortex	UBERON:0000451	97.58	gold quality
right frontal lobe	UBERON:0002810	96.79	gold quality
orbitofrontal cortex	UBERON:0004167	96.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.02	gold quality
frontal cortex	UBERON:0001870	96.00	gold quality
Ammon’s horn	UBERON:0001954	95.85	gold quality
forebrain	UBERON:0001890	95.83	gold quality
hypothalamus	UBERON:0001898	95.66	gold quality
telencephalon	UBERON:0001893	95.63	gold quality
neocortex	UBERON:0001950	95.50	gold quality
temporal lobe	UBERON:0001871	95.37	gold quality
cerebral cortex	UBERON:0000956	95.25	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.24	gold quality
CA1 field of hippocampus	UBERON:0003881	94.85	gold quality
cingulate cortex	UBERON:0003027	94.78	gold quality
anterior cingulate cortex	UBERON:0009835	94.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.49	gold quality
brain	UBERON:0000955	94.46	gold quality
entorhinal cortex	UBERON:0002728	94.24	gold quality
central nervous system	UBERON:0001017	94.11	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	6614.61
E-HCAD-5	yes	6021.44
E-MTAB-9154	yes	5542.06
E-MTAB-10485	yes	3520.47
E-HCAD-56	yes	2905.92
E-MTAB-8221	yes	1147.03
E-GEOD-124472	yes	772.87
E-GEOD-114530	yes	690.65
E-HCAD-10	yes	617.54
E-MTAB-9388	yes	12.04
E-MTAB-10042	no	615.17
E-MTAB-6524	no	89.21
E-CURD-11	no	2.88
E-ANND-3	no	2.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NEUROD1

miRNA regulators (miRDB)

66 targeting NNAT, 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-6825-5P	99.96	69.81	3431
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-302A-5P	99.39	68.21	1913
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-5001-5P	99.05	66.76	1972

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia (PMID:11960906)
• Neuronatin expression is associated with poor prognosis in patients with adenocarcinoma, and may be useful as a prognostic marker for lung adenocarcinoma. (PMID:17805055)
• frequently observed overexpression of both neuronatin splice forms in medulloblastomaenhances growth in this cancer (PMID:18701710)
• Loss of neuronatin expression is associated with promoter hypermethylation in pituitary adenoma. (PMID:19218280)
• A putative role of Nnat in human energy homeostasis is further emphasized by a consistent association between single nucleotide polymorphisms (SNPs) in the human Nnat gene and severe childhood and adult obesity (PMID:19851307)
• malin negatively regulates neuronatin and its loss of function in Lafora disease results in increased accumulation of neuronatin (PMID:21742036)
• A stringent analysis identified NNAT as a key imprinted gene that was dysregulated in induced pluripotent stem cells. (PMID:22022350)
• Neuronatin in a subset of glioblastoma multiforme tumor progenitor cells is associated with increased cell proliferation and shorter patient survival. (PMID:22624064)
• Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease (PMID:23408434)
• methylation status of a not-yet-described regulatory element within the NNAT locus that contains four potential CTCF binding sites determines the expression level of NNAT (PMID:23825673)
• indicate that Nnat is related to keratinocyte differentiation by up-regulating involucrin expression (PMID:24252747)
• Data suggest NNAT as a potential tumor suppressor in myxoid liposarcomas. (PMID:24345474)
• Neuronatin gene: Imprinted and misfolded: Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss. (PMID:24345642)
• The authors found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer) in patients with medullary thyroid cancer. (PMID:28181547)
• NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa. (PMID:30933048)
• The predictive potential of Neuronatin for neoadjuvant chemotherapy of breast cancer. (PMID:34092612)
• In silico identification of the rare-coding pathogenic mutations and structural modeling of human NNAT gene associated with anorexia nervosa. (PMID:35655118)
• DNA methylation-mediated silencing of Neuronatin promotes hepatocellular carcinoma proliferation through the PI3K-Akt signaling pathway. (PMID:36473542)
• NNAT is a novel mediator of oxidative stress that suppresses ER + breast cancer. (PMID:37400769)
• Understanding the impact of structural modifications at the NNAT gene’s post-translational acetylation site: in silico approach for predicting its drug-interaction role in anorexia nervosa. (PMID:37987927)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Neuronatin — Q16517 (reviewed: Q16517)

All UniProt accessions (4): A0A3B3IRP3, A0A3B3IS74, A0A3B3ITN5, Q16517

UniProt curated annotations — full annotation on UniProt →

Function. May participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system. May function as a regulatory subunit of ion channels.

Similarity. Belongs to the neuronatin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16517-1	Alpha	yes
Q16517-2	Beta

RefSeq proteins (3): NP_001309731, NP_005377, NP_859017 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024885	Neuronatin	Family

UniProt features (3 total): chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16517-F1	68.32	0.00

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 236 (showing top): GGGACCA_MIR133A_MIR133B, TSENG_IRS1_TARGETS_UP, TGCGCANK_UNKNOWN, LI_WILMS_TUMOR, GCANCTGNY_MYOD_Q6, BECKER_TAMOXIFEN_RESISTANCE_UP, MODULE_45, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, GOBP_CELL_CELL_SIGNALING, MODULE_66

GO Biological Process (3): brain development (GO:0007420), protein lipoylation (GO:0009249), positive regulation of insulin secretion (GO:0032024)

GO Molecular Function (0):

GO Cellular Component (2): cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
central nervous system development	1
animal organ development	1
head development	1
peptidyl-lysine modification	1
protein maturation	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NNAT	BLCAP	P62952	968
NNAT	GNAS	Q5JWF2	735
NNAT	MEST	Q5EB52	717
NNAT	IGF2	P01344	703
NNAT	PEG10	Q86TG7	701
NNAT	PLAGL1	Q9UM63	697
NNAT	SGCE	O43556	690
NNAT	NAP1L5	Q96NT1	680
NNAT	SNRPN	P14648	650
NNAT	PEG3	P78418	621
NNAT	GRB10	Q13322	601
NNAT	NDN	Q99608	584
NNAT	DLK1	P15803	583
NNAT	MCTS2	A0A3B3IRV3	571
NNAT	IGF2R	P11717	548
NNAT	PTH1R	Q03431	548

IntAct

2 interactions, top by confidence:

A	B	Type	Score
yapF	NNAT	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): NNAT (Negative Genetic), NNAT (Two-hybrid), NHLRC1 (Affinity Capture-Western), APP (Reconstituted Complex)

ESM2 similar proteins: A0A023PYH5, A0A023PZL2, A0ZZ55, B2Y1W5, C0H425, G2TRL0, O21039, O78514, O94341, P0AAA5, P0AAA6, P0C5R1, P10348, P20557, P34702, P38317, P40539, P43566, P46879, P48105, P50943, P51325, P52366, P52547, P59634, P81331, Q03783, Q06J16, Q0Q043, Q0Q471, Q16517, Q1ACL6, Q1XDG1, Q2JLQ8, Q32RP3, Q3I5J1, Q3LZX8, Q3ZBS9, Q5SCX1, Q61979

Diamond homologs: Q0Q043, Q16517, Q3ZBS9, Q61979, Q62649, Q6JL78

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 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

461 predictions. Top by Δscore:

Variant	Effect	Δscore
20:37521403:GGTA:G	donor_loss	0.9900
20:37521404:G:GA	donor_loss	0.9900
20:37521405:T:G	donor_loss	0.9900
20:37521400:GCAG:G	donor_gain	0.9800
20:37521404:G:GG	donor_gain	0.9800
20:37522666:GGT:G	acceptor_gain	0.9600
20:37522663:GCA:G	acceptor_loss	0.9500
20:37522664:CA:C	acceptor_loss	0.9500
20:37522665:A:AT	acceptor_loss	0.9500
20:37521401:CAG:C	donor_gain	0.9400
20:37522529:C:G	donor_gain	0.9400
20:37521318:CCATT:C	donor_gain	0.9300
20:37521399:TGCAG:T	donor_gain	0.9200
20:37521400:GCAGG:G	donor_gain	0.9200
20:37522562:G:GT	donor_gain	0.9200
20:37521402:AG:A	donor_gain	0.9100
20:37521403:GG:G	donor_gain	0.9100
20:37522431:GAA:G	donor_gain	0.9100
20:37521686:GCG:G	donor_gain	0.9000
20:37522434:G:GG	donor_gain	0.9000
20:37522665:A:AG	acceptor_gain	0.8900
20:37522666:G:GG	acceptor_gain	0.8900
20:37521325:TGGA:T	donor_gain	0.8800
20:37522431:G:GT	donor_gain	0.8800
20:37522665:AGGTG:A	acceptor_gain	0.8800
20:37522662:CGCAG:C	acceptor_gain	0.8600
20:37522663:GCAGG:G	acceptor_gain	0.8600
20:37521689:G:GG	donor_gain	0.8500
20:37522437:AG:A	donor_gain	0.8500
20:37522438:GG:G	donor_gain	0.8500

AlphaMissense

502 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:37521377:T:A	W16R	0.996
20:37521377:T:C	W16R	0.996
20:37521374:G:C	G15R	0.995
20:37521375:G:A	G15D	0.994
20:37521363:T:C	L11P	0.992
20:37521366:T:A	L12H	0.991
20:37522370:T:C	C29R	0.991
20:37522373:T:C	C30R	0.987
20:37522391:T:C	F36L	0.987
20:37522393:C:A	F36L	0.987
20:37522393:C:G	F36L	0.987
20:37521359:G:A	E10K	0.986
20:37521390:G:C	R20P	0.984
20:37522367:G:A	E28K	0.982
20:37521380:T:C	Y17H	0.980
20:37521389:C:A	R20S	0.980
20:37521369:T:A	I13N	0.979
20:37521363:T:A	L11Q	0.978
20:37521366:T:C	L12P	0.978
20:37521372:T:A	I14N	0.978
20:37521399:T:C	L23P	0.978
20:37522368:A:T	E28V	0.978
20:37522365:T:C	L27P	0.976
20:37521357:C:A	A9D	0.975
20:37522397:T:C	F38L	0.973
20:37522399:T:A	F38L	0.973
20:37522399:T:G	F38L	0.973
20:37522670:T:C	F53L	0.973
20:37522672:C:A	F53L	0.973
20:37522672:C:G	F53L	0.973

dbSNP variants (sampled 300 via entrez): RS1000075729 (20:37519404 CAAAAAAAAAAAAAAAAAAAGAAAAAA>C,CAA,CAAA,CAAAA,CAAAAA,CAAAAAA), RS1000860076 (20:37523589 C>T), RS1001312036 (20:37523894 G>A), RS1001895485 (20:37520105 C>A), RS1002304718 (20:37523008 G>A,C), RS1002450186 (20:37519904 G>A), RS1003739849 (20:37521599 T>C,G), RS1005108296 (20:37521185 C>A,T), RS1005377732 (20:37520829 C>T), RS1006061932 (20:37519891 C>G,T), RS1006868358 (20:37523010 TA>T), RS1007054693 (20:37523970 T>A,C), RS1007392512 (20:37523281 C>T), RS1007723980 (20:37519778 C>T), RS1008060720 (20:37522342 G>A)

Disease associations

OMIM: gene MIM:603106 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression	2
di-n-butylphosphoric acid	affects expression	1
4-hydroxy-equilenin	decreases expression	1
licochalcone B	increases expression	1
jinfukang	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Ethanol	decreases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	increases expression	1
Diazinon	increases methylation	1
Ellagic Acid	increases expression	1
Folic Acid	affects cotreatment, decreases expression	1
Lidocaine	decreases expression, decreases reaction	1
Niclosamide	decreases expression	1
Oxygen	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	decreases expression	1
Valproic Acid	increases expression	1
Thapsigargin	decreases expression	1

Clinical trials (associated diseases)

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