NUDT6

Summary

NUDT6 (nudix hydrolase 6, HGNC:8053) is a protein-coding gene on chromosome 4q28.1, encoding Nudix hydrolase 6 (P53370). Mediates the hydrolysis of some nucleoside diphosphate derivatives, such as NADH and FAD (in vitro).

This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11162 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 33 total — 1 pathogenic
• MANE Select transcript: NM_007083

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8053
Approved symbol	NUDT6
Name	nudix hydrolase 6
Location	4q28.1
Locus type	gene with protein product
Status	Approved
Aliases	gfg-1, gfg, FGF2AS, FGF-AS
Ensembl gene	ENSG00000170917
Ensembl biotype	protein_coding
OMIM	606261
Entrez	11162

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 4 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000304430, ENST00000339154, ENST00000502270, ENST00000503370, ENST00000510735, ENST00000512116, ENST00000513517, ENST00000608639

RefSeq mRNA: 2 — MANE Select: NM_007083 NM_007083, NM_198041

CCDS: CCDS3729, CCDS43268

Canonical transcript exons

ENST00000304430 — 5 exons

Exon	Start	End
ENSE00002316307	122922335	122922597
ENSE00003518972	122917501	122917704
ENSE00003559854	122912568	122912623
ENSE00003582912	122897624	122897678
ENSE00003895180	122892577	122893225

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 91.49.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.4611 / max 58.5584, expressed in 1611 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53851	3.5682	1516
53852	0.8929	507

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	91.49	gold quality
medial globus pallidus	UBERON:0002477	89.08	gold quality
right lobe of liver	UBERON:0001114	87.92	gold quality
germinal epithelium of ovary	UBERON:0001304	86.03	gold quality
globus pallidus	UBERON:0001875	85.55	gold quality
tendon	UBERON:0000043	84.47	gold quality
liver	UBERON:0002107	84.36	gold quality
oocyte	CL:0000023	84.32	gold quality
heart left ventricle	UBERON:0002084	84.09	gold quality
right adrenal gland	UBERON:0001233	84.08	gold quality
cardiac ventricle	UBERON:0002082	84.07	gold quality
right adrenal gland cortex	UBERON:0035827	83.81	gold quality
heart right ventricle	UBERON:0002080	83.26	gold quality
left adrenal gland	UBERON:0001234	83.00	gold quality
left adrenal gland cortex	UBERON:0035825	82.85	gold quality
renal medulla	UBERON:0000362	82.74	gold quality
adrenal cortex	UBERON:0001235	82.71	gold quality
right uterine tube	UBERON:0001302	82.34	gold quality
adrenal gland	UBERON:0002369	81.75	gold quality
heart	UBERON:0000948	81.72	gold quality
calcaneal tendon	UBERON:0003701	81.69	gold quality
apex of heart	UBERON:0002098	81.61	gold quality
biceps brachii	UBERON:0001507	81.52	gold quality
cerebellar vermis	UBERON:0004720	80.82	silver quality
right atrium auricular region	UBERON:0006631	80.75	gold quality
adult mammalian kidney	UBERON:0000082	80.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.49	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.39	gold quality
secondary oocyte	CL:0000655	80.19	gold quality
parietal pleura	UBERON:0002400	80.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

10 targeting NUDT6, 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-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-1298-5P	95.96	64.81	573

Literature-anchored findings (GeneRIF, showing 6)

• FGF-2 exhibits antitumor activity in vitro and correlates with expression of FGF receptors expression in medulloblastoma cells (PMID:11801566)
• 18-kDa FGF-2 harbors a C-terminal nonclassical bipartite nuclear localization signal, a portion of which also regulates its nucleolar localization. (PMID:15247275)
• The aim of this study was to characterize the expression of alternatively spliced FGF-AS transcripts and encoded nudix-motif proteins in normal human tissues and in esophageal adenocarcinoma. (PMID:17569023)
• hydroxyapatite nanocrystals exposure up-regulated FGF-2 mRNA by 6 fold and increased 18 kDa protein isoform by 40% (PMID:17681892)
• Thus, survivin, Smac, and PKC alpha might play important roles in the inhibition of apoptosis by FGF-2 in human small cell lung cancer cells. (PMID:18401527)
• NUDT6 and NUDT9, two mitochondrial members of the NUDIX family, have distinct hydrolysis activities. (PMID:37343711)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nudt6	ENSDARG00000103523
mus_musculus	Nudt6	ENSMUSG00000050174
rattus_norvegicus	Nudt6	ENSRNOG00000017420
drosophila_melanogaster	CG8128	FBGN0030668

Protein

Protein identifiers

Nudix hydrolase 6 — P53370 (reviewed: P53370)

Alternative names: Antisense basic fibroblast growth factor, FAD diphosphatase NUDT6, NADH pyrophosphatase NUDT6, Nucleoside diphosphate-linked moiety X motif 6, Protein GFG

All UniProt accessions (3): P53370, E9PBZ9, H0Y9C0

UniProt curated annotations — full annotation on UniProt →

Function. Mediates the hydrolysis of some nucleoside diphosphate derivatives, such as NADH and FAD (in vitro). May contribute to the regulation of cell proliferation.

Subunit / interactions. Monomer and homodimer.

Subcellular location. Mitochondrion Nucleus. Cytoplasm.

Tissue specificity. Detected in liver, kidney and esophagus (at protein level). Ubiquitous.

Activity regulation. Mn(2+) has a strong inhibitory effet on ADP-ribose diphosphatase activity.

Miscellaneous. This protein is coded from a FGF2 (BFGF) gene antisense transcript.

Similarity. Belongs to the Nudix hydrolase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P53370-1	1, B	yes
P53370-2	2, A

RefSeq proteins (2): NP_009014, NP_932158 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000086	NUDIX_hydrolase_dom	Domain
IPR003293	Nudix_hydrolase6-like	Family
IPR015797	NUDIX_hydrolase-like_dom_sf	Homologous_superfamily
IPR020084	NUDIX_hydrolase_CS	Conserved_site
IPR040618	Pre-Nudix	Domain

Pfam: PF00293, PF18290

Catalyzed reactions (Rhea), 2 shown:

• FAD + H2O = FMN + AMP + 2 H(+) (RHEA:13889)
• NADH + H2O = reduced beta-nicotinamide D-ribonucleotide + AMP + 2 H(+) (RHEA:48868)

UniProt features (45 total): strand 15, sequence conflict 12, helix 9, turn 3, sequence variant 2, chain 1, domain 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3H95	X-RAY DIFFRACTION	1.7
3FXT	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P53370-F1	86.89	0.78

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_REGULATION_OF_CELL_CYCLE, OCT1_07, DANG_BOUND_BY_MYC, CHIANG_LIVER_CANCER_SUBCLASS_CTNNB1_UP, CHIANG_LIVER_CANCER_SUBCLASS_PROLIFERATION_DN, BENPORATH_MYC_MAX_TARGETS, SCGGAAGY_ELK1_02, KIM_WT1_TARGETS_DN, YATGNWAAT_OCT_C, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, GOMF_NAD_BINDING, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (2): negative regulation of cell population proliferation (GO:0008285), negative regulation of cell cycle (GO:0045786)

GO Molecular Function (5): NADH pyrophosphatase activity (GO:0035529), ADP-ribose diphosphatase activity (GO:0047631), FAD diphosphatase activity (GO:0047884), NAD binding (GO:0051287), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cellular process	2
dinucleotide phosphatase activity	2
intracellular membrane-bounded organelle	2
cell population proliferation	1
regulation of cell population proliferation	1
cell cycle	1
regulation of cell cycle	1
pyrophosphatase activity	1
adenyl nucleotide binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

642 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUDT6	HDGF	P51858	762
NUDT6	FGF2	P09038	666
NUDT6	FGF13	Q92913	625
NUDT6	NUDT22	Q9BRQ3	591
NUDT6	AFG2A	Q8NB90	579
NUDT6	NUDT17	P0C025	572
NUDT6	GATA4	P43694	554
NUDT6	IKZF1	Q13422	549
NUDT6	NUDT18	Q6ZVK8	545
NUDT6	NUDT12	Q9BQG2	533
NUDT6	NUDT5	Q9UKK9	527
NUDT6	NUDT14	O95848	512
NUDT6	NUDT3	O95989	495
NUDT6	NUDT15	Q9NV35	494
NUDT6	NUDT2	P50583	486

IntAct

10 interactions, top by confidence:

A	B	Type	Score
NUDT6	DENR	psi-mi:“MI:0914”(association)	0.530
MRPS18C	MRPS14	psi-mi:“MI:0914”(association)	0.530
TINAG	VPS26A	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
NUDT6	SCHIP1	psi-mi:“MI:0915”(physical association)	0.000
NUDT6	UBA1	psi-mi:“MI:0220”(ubiquitination reaction)	0.000

BioGRID (36): MTIF2 (Affinity Capture-MS), PM20D2 (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), GLDC (Affinity Capture-MS), UBLCP1 (Affinity Capture-MS), NRGN (Affinity Capture-MS), DENR (Affinity Capture-MS), BOLA3 (Affinity Capture-MS), UBR2 (Affinity Capture-MS), NUDT6 (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), NRGN (Affinity Capture-MS), BOLA3 (Affinity Capture-MS), UBLCP1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMH2, A1L251, A2ARP1, A7Z050, D3ZEY4, E7FCP8, E9QAM5, O00562, O35954, O42412, O95822, P0C644, P0C7A1, P12617, P16386, P40935, P49898, P49899, P52824, P53370, P54310, P70563, Q17QN2, Q2KI24, Q3URQ7, Q499U8, Q5EU90, Q5I0I8, Q5RAR6, Q5RDF1, Q5TGY1, Q5U2N3, Q5XIL6, Q68J42, Q6P5E8, Q6PD24, Q6PFW1, Q80YU0, Q8BX80, Q8CH40

Diamond homologs: A0A024RBG1, A2VE79, O95989, P0C027, P0C028, P53370, P70563, P96590, Q09790, Q52K88, Q566C7, Q58CW0, Q5RAF0, Q8CH40, Q8NFP7, Q8R2U6, Q8VY81, Q93ZY7, Q96G61, Q99321, Q99MY2, Q9JI46, Q9LE73, Q9LHK1, Q9LQU5, Q9NZJ9, Q9ZU95, Q9RVK2, P32091, P59659, A8LKJ8, P13420, Q16BL5, Q1GSV9, Q2G7H8, Q5LMH8, Q6NPD7, Q75UV1, Q8GW31, Q8L7W2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	26
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1075381	NC_000004.11:g.(?123663028)(124235239_?)del	Pathogenic

SpliceAI

859 predictions. Top by Δscore:

Variant	Effect	Δscore
4:122892210:GAAAT:G	acceptor_gain	1.0000
4:122893223:CTC:C	acceptor_gain	1.0000
4:122893225:CCT:C	acceptor_loss	1.0000
4:122893227:T:C	acceptor_loss	1.0000
4:122893230:G:C	acceptor_gain	1.0000
4:122897679:C:CC	acceptor_gain	1.0000
4:122912560:CAGCT:C	donor_loss	1.0000
4:122912561:AGCTT:A	donor_loss	1.0000
4:122912562:GCTT:G	donor_loss	1.0000
4:122912563:CTT:C	donor_loss	1.0000
4:122912564:TTA:T	donor_loss	1.0000
4:122912565:T:TG	donor_loss	1.0000
4:122912566:A:AC	donor_gain	1.0000
4:122912566:AC:A	donor_loss	1.0000
4:122912567:C:CG	donor_gain	1.0000
4:122892205:TTTCA:T	acceptor_loss	0.9900
4:122892206:TTCA:T	acceptor_loss	0.9900
4:122892207:TCA:T	acceptor_loss	0.9900
4:122892208:CAGAA:C	acceptor_loss	0.9900
4:122892209:A:AG	acceptor_gain	0.9900
4:122892209:AGA:A	acceptor_loss	0.9900
4:122892210:G:GG	acceptor_gain	0.9900
4:122892210:GA:G	acceptor_gain	0.9900
4:122892210:GAA:G	acceptor_gain	0.9900
4:122893221:GTCTC:G	acceptor_gain	0.9900
4:122893222:TCTC:T	acceptor_gain	0.9900
4:122893223:CTCC:C	acceptor_gain	0.9900
4:122893224:TC:T	acceptor_gain	0.9900
4:122893224:TCCT:T	acceptor_gain	0.9900
4:122893225:CC:C	acceptor_gain	0.9900

AlphaMissense

2017 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:122893158:A:C	S207R	0.988
4:122893158:A:T	S207R	0.988
4:122893160:T:G	S207R	0.988
4:122893035:C:A	W248C	0.984
4:122893035:C:G	W248C	0.984
4:122893037:A:G	W248R	0.983
4:122893037:A:T	W248R	0.983
4:122893173:G:C	F202L	0.974
4:122893173:G:T	F202L	0.974
4:122893175:A:G	F202L	0.974
4:122893153:C:G	R209P	0.973
4:122922414:G:C	F53L	0.973
4:122922414:G:T	F53L	0.973
4:122922416:A:G	F53L	0.973
4:122893096:C:G	R228P	0.972
4:122893210:C:G	R190P	0.972
4:122917620:G:T	A108D	0.971
4:122893169:A:G	S204P	0.970
4:122917605:A:G	F113S	0.969
4:122893100:A:G	C227R	0.968
4:122897666:A:G	W171R	0.968
4:122897666:A:T	W171R	0.968
4:122912587:A:T	V160D	0.968
4:122917604:G:C	F113L	0.967
4:122917604:G:T	F113L	0.967
4:122917606:A:G	F113L	0.967
4:122893098:G:C	C227W	0.962
4:122893216:G:T	A188E	0.962
4:122893125:A:C	F218L	0.959
4:122893125:A:T	F218L	0.959

dbSNP variants (sampled 300 via entrez): RS1000181930 (4:122904291 T>C), RS1000299804 (4:122894792 A>T), RS1000316321 (4:122908448 G>T), RS1000319587 (4:122904645 G>C), RS1000490049 (4:122910566 T>C), RS1000506368 (4:122900008 C>T), RS1000632355 (4:122893208 C>A), RS1000648536 (4:122907120 C>A), RS1000845110 (4:122921440 T>C), RS1000876044 (4:122921194 G>A,T), RS1001154506 (4:122899564 C>A), RS1001168445 (4:122924010 A>G,T), RS1001214057 (4:122900300 A>C,G), RS1001306102 (4:122903943 G>A), RS1001314500 (4:122901406 T>C)

Disease associations

OMIM: gene MIM:606261 | disease phenotypes: MIM:616577

GenCC curated gene-disease

Mondo (1): microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (MONDO:0014698)

Orphanet (1): Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome (Orphanet:457351)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002436_2	Irritable bowel syndrome	8.000000e-08
GCST006867_35	Type 2 diabetes	2.000000e-08
GCST90000025_284	Appendicular lean mass	3.000000e-30

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	6
bisphenol A	decreases expression, affects cotreatment, increases expression	2
sodium arsenite	affects expression, decreases expression	2
Estradiol	decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Cyclosporine	decreases expression	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	increases abundance, increases expression	1
jinfukang	decreases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Cisplatin	decreases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	increases expression, affects cotreatment	1
Manganese	increases abundance, increases expression	1
Phthalic Acids	increases methylation	1
Progesterone	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_DX51	HAP1 NUDT6 (-) NUDT9 (-)	Cancer cell line	Male
CVCL_TB42	HAP1 NUDT6 (-) 1	Cancer cell line	Male
CVCL_TB43	HAP1 NUDT6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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