PUS3

Summary

PUS3 (pseudouridine synthase 3, HGNC:25461) is a protein-coding gene on chromosome 11q24.2, encoding tRNA pseudouridine(38/39) synthase (Q9BZE2). Formation of pseudouridine at position 39 in the anticodon stem and loop of transfer RNAs.

The protein encoded by this gene catalyzes the formation of tRNA pseudouridine from tRNA uridine at position 39 in the anticodon stem and loop of transfer RNAs. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 83480 — RefSeq curated summary.

At a glance

• Gene–disease (curated): severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 31 total — 6 likely-pathogenic
• Phenotypes (HPO): 47
• MANE Select transcript: NM_031307

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25461
Approved symbol	PUS3
Name	pseudouridine synthase 3
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FKSG32, DEG1
Ensembl gene	ENSG00000110060
Ensembl biotype	protein_coding
OMIM	616283
Entrez	83480

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000227474, ENST00000529801, ENST00000530811, ENST00000534158, ENST00000613398, ENST00000937564

RefSeq mRNA: 2 — MANE Select: NM_031307 NM_001271985, NM_031307

CCDS: CCDS73411, CCDS8466

Canonical transcript exons

ENST00000227474 — 4 exons

Exon	Start	End
ENSE00003844598	125903170	125903206
ENSE00003893046	125895224	125895789
ENSE00003893820	125893485	125894286
ENSE00003895890	125895907	125896330

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 92.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9742 / max 132.9588, expressed in 1741 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
123009	7.9742	1741

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.52	gold quality
islet of Langerhans	UBERON:0000006	90.23	gold quality
sperm	CL:0000019	88.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.19	gold quality
male germ cell	CL:0000015	87.40	gold quality
right lobe of liver	UBERON:0001114	86.93	gold quality
liver	UBERON:0002107	86.75	gold quality
pancreas	UBERON:0001264	86.54	gold quality
tongue squamous epithelium	UBERON:0006919	86.32	silver quality
body of pancreas	UBERON:0001150	86.08	gold quality
hair follicle	UBERON:0002073	85.28	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.15	gold quality
gastrocnemius	UBERON:0001388	84.04	gold quality
muscle of leg	UBERON:0001383	83.45	gold quality
cortical plate	UBERON:0005343	83.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.31	gold quality
muscle organ	UBERON:0001630	82.66	gold quality
skeletal muscle organ	UBERON:0014892	82.66	gold quality
leukocyte	CL:0000738	82.17	gold quality
monocyte	CL:0000576	82.15	gold quality
mononuclear cell	CL:0000842	82.09	gold quality
pericardium	UBERON:0002407	81.50	gold quality
ganglionic eminence	UBERON:0004023	81.44	gold quality
biceps brachii	UBERON:0001507	81.32	gold quality
smooth muscle tissue	UBERON:0001135	80.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	80.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	80.74	gold quality
body of stomach	UBERON:0001161	80.71	gold quality
superficial temporal artery	UBERON:0001614	80.55	gold quality
skeletal muscle tissue	UBERON:0001134	80.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

18 targeting PUS3, 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-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-384	98.71	67.34	1229
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-7975	95.04	66.76	516
HSA-MIR-6802-5P	94.94	65.95	366

Literature-anchored findings (GeneRIF, showing 4)

• Consistent with the known role of Pus3 in isomerizing uracil to pseudouridine at positions 38 and 39 in tRNA, we found a significant reduction in this post-transcriptional modification of tRNA in patient cells (PMID:27055666)
• Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders. (PMID:34415064)
• Destabilization of mutated human PUS3 protein causes intellectual disability. (PMID:36125428)
• The molecular basis of tRNA selectivity by human pseudouridine synthase 3. (PMID:38996458)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pus3	ENSDARG00000028976
mus_musculus	Pus3	ENSMUSG00000032103
rattus_norvegicus	Pus3	ENSRNOG00000012994
drosophila_melanogaster	CG3045	FBGN0034703
caenorhabditis_elegans		WBGENE00006473

Paralogs (2): PUSL1 (ENSG00000169972), PUS1 (ENSG00000177192)

Protein

Protein identifiers

tRNA pseudouridine(38/39) synthase — Q9BZE2 (reviewed: Q9BZE2)

Alternative names: tRNA pseudouridine synthase 3, tRNA pseudouridylate synthase 3, tRNA-uridine isomerase 3

All UniProt accessions (4): A0A087WY59, E9PNY6, Q9BZE2, E9PRI9

UniProt curated annotations — full annotation on UniProt →

Function. Formation of pseudouridine at position 39 in the anticodon stem and loop of transfer RNAs.

Subcellular location. Nucleus.

Disease relevance. Neurodevelopmental disorder with microcephaly and gray sclerae (NEDMIGS) [MIM:617051] An autosomal recessive disorder characterized by global developmental delay, hypotonia, profoundly impaired intellectual development with poor or absent language, mild microcephaly, abnormal visual fixation, and seizures in most patients. Affected individuals also have gray sclerae. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tRNA pseudouridine synthase TruA family.

RefSeq proteins (2): NP_001258914, NP_112597* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001406	PsdUridine_synth_TruA	Family
IPR020094	TruA/RsuA/RluB/E/F_N	Homologous_superfamily
IPR020095	PsdUridine_synth_TruA_C	Homologous_superfamily
IPR020097	PsdUridine_synth_TruA_a/b_dom	Domain
IPR020103	PsdUridine_synth_cat_dom_sf	Homologous_superfamily
IPR041707	Pus3-like	Family

Pfam: PF01416

Catalyzed reactions (Rhea), 1 shown:

• uridine(38/39) in tRNA = pseudouridine(38/39) in tRNA (RHEA:42564)

UniProt features (42 total): helix 14, strand 10, turn 4, modified residue 4, sequence variant 3, initiator methionine 1, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1, active site 1, binding site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9ENB	ELECTRON MICROSCOPY	2.66
9ENF	ELECTRON MICROSCOPY	2.97
8OKD	ELECTRON MICROSCOPY	3.1
9ENE	ELECTRON MICROSCOPY	3.15
9ENC	ELECTRON MICROSCOPY	3.36
9F9Q	ELECTRON MICROSCOPY	6.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZE2-F1	84.05	0.64

Functional residue map

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

Catalytic / active sites (1): 118 (nucleophile)

Ligand- & substrate-binding residues (1): 195

Post-translational modifications (4): 2, 456, 466, 468

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol

MSigDB gene sets: 226 (showing top): GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, AACYNNNNTTCCS_UNKNOWN, GOBP_MRNA_MODIFICATION, GOBP_PSEUDOURIDINE_SYNTHESIS, GOBP_RNA_MODIFICATION, AMIT_EGF_RESPONSE_120_HELA, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_TRNA_PROCESSING, NRSF_01, REACTOME_METABOLISM_OF_RNA, GOBP_TRNA_MODIFICATION, STAT1_02, GOMF_PSEUDOURIDINE_SYNTHASE_ACTIVITY

GO Biological Process (6): tRNA modification (GO:0006400), tRNA pseudouridine synthesis (GO:0031119), mRNA pseudouridine synthesis (GO:1990481), pseudouridine synthesis (GO:0001522), tRNA processing (GO:0008033), RNA modification (GO:0009451)

GO Molecular Function (5): RNA binding (GO:0003723), pseudouridine synthase activity (GO:0009982), tRNA pseudouridine(38/39) synthase activity (GO:0160154), isomerase activity (GO:0016853), tRNA pseudouridine(38-40) synthase activity (GO:0160147)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA modification	2
pseudouridine synthesis	2
tRNA pseudouridine synthase activity	2
cellular anatomical structure	2
tRNA processing	1
tRNA modification	1
mRNA modification	1
RNA processing	1
tRNA metabolic process	1
RNA metabolic process	1
macromolecule modification	1
nucleic acid binding	1
intramolecular transferase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2116 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PUS3	TRUB1	Q8WWH5	838
PUS3	PUS7	Q96PZ0	809
PUS3	PUS7L	Q9H0K6	773
PUS3	RPUSD2	Q8IZ73	767
PUS3	RPUSD1	Q9UJJ7	766
PUS3	PUS10	Q3MIT2	756
PUS3	RPUSD3	Q6P087	735
PUS3	RPUSD4	Q96CM3	730
PUS3	TRUB2	O95900	717
PUS3	FTSJ1	Q9UET6	690
PUS3	WDR4	P57081	666
PUS3	TRMT1	Q9NXH9	666
PUS3	PUS1	Q9Y606	652
PUS3	TRMT10A	Q8TBZ6	635
PUS3	ADAT3	Q96EY9	597

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
PDZK1	PUS3	psi-mi:“MI:0407”(direct interaction)	0.440
PRKAB2	RFC1	psi-mi:“MI:0914”(association)	0.350
MAP2K4	PRKCZ	psi-mi:“MI:0914”(association)	0.350
MAD2L1	MED19	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): PUS3 (Two-hybrid), PUS3 (Negative Genetic), PUS3 (Affinity Capture-MS), PUS3 (Proximity Label-MS), PUS3 (Affinity Capture-MS), PUS3 (Affinity Capture-MS), PUS3 (Affinity Capture-MS), PUS3 (Cross-Linking-MS (XL-MS)), PUS3 (Cross-Linking-MS (XL-MS)), PUS3 (Affinity Capture-RNA)

ESM2 similar proteins: A3GH78, A6ZVS0, A7A1S5, A7TSV4, A8WZU5, O22928, O74343, O74451, O94295, O94396, O94443, O94536, P31115, P32783, P40562, P40848, P48567, P53167, P87175, Q02792, Q06053, Q06698, Q08647, Q09524, Q10988, Q12211, Q19546, Q3SX07, Q59S63, Q5A1A0, Q5AMG5, Q6BNU7, Q6CC39, Q6CKI0, Q6CKI1, Q6CKX0, Q6CQX2, Q6CWQ8, Q6FKN6, Q6FPQ3

Diamond homologs: A0ALT4, A0B7V0, A0KLN7, A1AUF4, A1BFF0, A1UZ38, A2S134, A2SU30, A3CXX4, A3DJK8, A3MBU2, A3NM70, A3P7N2, A4SE87, A4XKB7, A5FVK4, A5GB00, A5IBF5, A5ULI2, A5USG0, A5VLH4, A6LLJ7, A6QJ61, A7NR34, A8F526, A8F9B7, A8YTB0, A8Z326, A9BGW7, B0R6V1, B2G8U7, B2JQE6, B2U6Z1, B3E0A0, B4SA76, B5EFM8, B6YTJ2, B7GJ99, B7IHS2, B8DB42

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	6
Uncertain significance	15
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3599135	NM_001134793.2(HYLS1):c.130C>T (p.Gln44Ter)	Likely pathogenic
3599139	NM_001134793.2(HYLS1):c.415C>T (p.Gln139Ter)	Likely pathogenic
3599141	NM_001134793.2(HYLS1):c.807_808del (p.Lys270fs)	Likely pathogenic
4816850	NM_001134793.2(HYLS1):c.182delinsCA (p.Arg61fs)	Likely pathogenic
4816853	NM_001134793.2(HYLS1):c.316_319delinsTAACAGATGAGTAACAGAT (p.Glu106_Val107delinsTer)	Likely pathogenic
4816856	NM_001134793.2(HYLS1):c.674C>G (p.Ser225Ter)	Likely pathogenic

SpliceAI

600 predictions. Top by Δscore:

Variant	Effect	Δscore
11:125894282:CCATA:C	acceptor_gain	1.0000
11:125894283:CATA:C	acceptor_gain	1.0000
11:125894283:CATAC:C	acceptor_gain	1.0000
11:125894285:TA:T	acceptor_gain	1.0000
11:125894287:C:CC	acceptor_gain	1.0000
11:125899342:A:AG	acceptor_gain	1.0000
11:125899342:AGAAG:A	acceptor_gain	1.0000
11:125899343:G:GG	acceptor_gain	1.0000
11:125899343:GAA:G	acceptor_gain	1.0000
11:125899343:GAAGG:G	acceptor_gain	1.0000
11:125894284:ATA:A	acceptor_gain	0.9900
11:125894285:TAC:T	acceptor_loss	0.9900
11:125894287:C:CA	acceptor_loss	0.9900
11:125899343:GA:G	acceptor_gain	0.9900
11:125899338:TTGCA:T	acceptor_loss	0.9800
11:125899339:TGCA:T	acceptor_loss	0.9800
11:125899341:CAG:C	acceptor_loss	0.9800
11:125899343:G:C	acceptor_loss	0.9800
11:125894284:ATACT:A	acceptor_gain	0.9700
11:125894286:ACT:A	acceptor_gain	0.9600
11:125895219:CTCA:C	donor_loss	0.9600
11:125895220:TCAC:T	donor_loss	0.9600
11:125895221:CACC:C	donor_loss	0.9600
11:125895222:A:AG	donor_loss	0.9600
11:125895901:CCTTA:C	donor_loss	0.9600
11:125895902:CTTAC:C	donor_loss	0.9600
11:125895903:TTACC:T	donor_loss	0.9600
11:125895904:TAC:T	donor_loss	0.9600
11:125895905:A:AT	donor_loss	0.9600
11:125895923:ACT:A	donor_gain	0.9600

AlphaMissense

3203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:125895932:T:A	D118V	1.000
11:125895339:G:C	H277D	0.999
11:125895346:G:C	F274L	0.999
11:125895346:G:T	F274L	0.999
11:125895348:A:G	F274L	0.999
11:125895598:G:C	C190W	0.999
11:125895604:G:C	F188L	0.999
11:125895604:G:T	F188L	0.999
11:125895606:A:G	F188L	0.999
11:125895608:C:A	R187M	0.999
11:125895931:A:C	D118E	0.999
11:125895931:A:T	D118E	0.999
11:125895932:T:C	D118G	0.999
11:125895932:T:G	D118A	0.999
11:125895933:C:G	D118H	0.999
11:125895938:C:G	R116T	0.999
11:125895451:C:A	R239S	0.998
11:125895451:C:G	R239S	0.998
11:125895452:C:A	R239M	0.998
11:125895452:C:G	R239T	0.998
11:125895490:A:C	C226W	0.998
11:125895590:C:G	R193P	0.998
11:125895611:G:T	A186D	0.998
11:125895917:G:T	A123D	0.998
11:125895919:A:C	S122R	0.998
11:125895919:A:T	S122R	0.998
11:125895921:T:G	S122R	0.998
11:125895937:T:A	R116S	0.998
11:125895937:T:G	R116S	0.998
11:125895941:C:T	G115E	0.998

dbSNP variants (sampled 300 via entrez): RS1000005758 (11:125896285 G>A), RS1000616545 (11:125900073 G>A,C), RS1000837239 (11:125901401 C>A), RS1001008009 (11:125904347 C>G), RS1001012886 (11:125894660 A>G), RS1001063674 (11:125894346 A>G), RS1001221569 (11:125898366 T>A,G), RS1001292387 (11:125901027 A>G,T), RS1002054222 (11:125903030 C>A,T), RS1002195154 (11:125896421 G>T), RS1002624115 (11:125904405 G>A), RS1002673493 (11:125904258 C>T), RS1002801569 (11:125898306 T>C), RS1003203145 (11:125894682 T>TA), RS1003855440 (11:125900397 G>A)

Disease associations

OMIM: gene MIM:616283 | disease phenotypes: MIM:617051, MIM:236680

GenCC curated gene-disease

Disease	Classification	Inheritance
severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome	Definitive	Autosomal recessive

Mondo (3): severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (MONDO:0014886), hydrolethalus syndrome 1 (MONDO:0009365), hydrolethalus syndrome (MONDO:0006037)

Orphanet (2): Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome (Orphanet:488627), Hydrolethalus (Orphanet:2189)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000280	Coarse facial features
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000592	Blue sclerae
HP:0000639	Nystagmus
HP:0000709	Psychosis
HP:0000718	Aggressive behavior
HP:0000961	Cyanosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001531	Failure to thrive in infancy
HP:0001970	Tubulointerstitial nephritis
HP:0002015	Dysphagia
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002141	Gait imbalance

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010796_3815	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C565504	Hydrolethalus Syndrome 1 (supp.)
C536079	Hydrolethalus syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Cisplatin	increases expression, decreases expression	2
Valproic Acid	affects expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
ICG 001	decreases expression	1
Temozolomide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Adenine	decreases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Atrazine	increases expression	1
Colchicine	decreases expression	1
Coumestrol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Etoposide	decreases expression	1
Gallic Acid	decreases expression	1
Hydrogen Peroxide	affects expression	1
Hydroxyurea	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1

Clinical trials (associated diseases)

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