PUS1

Summary

PUS1 (pseudouridine synthase 1, HGNC:15508) is a protein-coding gene on chromosome 12q24.33, encoding Pseudouridylate synthase 1 homolog (Q9Y606). Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs.

This gene encodes a pseudouridine synthase that converts uridine to pseudouridine once it has been incorporated into an RNA molecule. The encoded enzyme may play an essential role in tRNA function and in stabilizing the secondary and tertiary structure of many RNAs. A mutation in this gene has been linked to mitochondrial myopathy and sideroblastic anemia. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 80324 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 581 total — 24 pathogenic, 29 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• MANE Select transcript: NM_025215

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15508
Approved symbol	PUS1
Name	pseudouridine synthase 1
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	MLASA1
Ensembl gene	ENSG00000177192
Ensembl biotype	protein_coding
OMIM	608109
Entrez	80324

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 retained_intron

ENST00000322060, ENST00000376649, ENST00000443358, ENST00000456665, ENST00000535067, ENST00000537484, ENST00000538037, ENST00000542167, ENST00000543754, ENST00000544213, ENST00000544662, ENST00000890860, ENST00000917732, ENST00000917733

RefSeq mRNA: 3 — MANE Select: NM_025215 NM_001002019, NM_001002020, NM_025215

CCDS: CCDS31928, CCDS9275

Canonical transcript exons

ENST00000376649 — 6 exons

Exon	Start	End
ENSE00001223968	131932175	131932312
ENSE00001471240	131929276	131929796
ENSE00002277032	131943539	131945896
ENSE00003622828	131929907	131930135
ENSE00003785301	131939173	131939275
ENSE00003787863	131941292	131941983

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 90.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6568 / max 160.3366, expressed in 1806 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128771	15.8216	1803
128770	0.9622	560
128769	0.8731	398

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	90.48	gold quality
mucosa of transverse colon	UBERON:0004991	89.60	gold quality
lower esophagus mucosa	UBERON:0035834	88.67	gold quality
right lobe of liver	UBERON:0001114	88.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.32	gold quality
spleen	UBERON:0002106	86.50	gold quality
esophagus mucosa	UBERON:0002469	86.42	gold quality
right adrenal gland	UBERON:0001233	86.33	gold quality
left adrenal gland	UBERON:0001234	86.26	gold quality
body of pancreas	UBERON:0001150	86.20	gold quality
left adrenal gland cortex	UBERON:0035825	86.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.05	gold quality
lower esophagus	UBERON:0013473	86.04	gold quality
esophagus	UBERON:0001043	85.96	gold quality
right adrenal gland cortex	UBERON:0035827	85.78	gold quality
body of stomach	UBERON:0001161	85.62	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.56	gold quality
skin of abdomen	UBERON:0001416	85.44	gold quality
adrenal cortex	UBERON:0001235	85.43	gold quality
transverse colon	UBERON:0001157	85.38	gold quality
lymph node	UBERON:0000029	85.02	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.86	gold quality
monocyte	CL:0000576	84.79	gold quality
skin of leg	UBERON:0001511	84.69	gold quality
nucleus accumbens	UBERON:0001882	84.63	gold quality
stromal cell of endometrium	CL:0002255	84.56	gold quality
mononuclear cell	CL:0000842	84.51	gold quality
leukocyte	CL:0000738	84.48	gold quality
apex of heart	UBERON:0002098	84.26	gold quality
left uterine tube	UBERON:0001303	84.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting PUS1, 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-548P	99.98	72.25	3784
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-3685	99.62	68.83	1621
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-655-5P	98.74	65.93	888
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-558	97.50	67.16	977

Literature-anchored findings (GeneRIF, showing 10)

• Missense mutation in pseudouridine synthase 1 causes mitochondrial myopathy and sideroblastic anemia (PMID:15108122)
• MLASA is associated with absent or greatly reduced tRNA pseudouridylation at specific sites, implicating this pathway in its molecular pathogenesis. (PMID:15772074)
• A new homozygous stop mutation (E220X)predicts a protein missing 208/427 amino acid residues on the C terminus. The nuclear isoform has an N-terminal extension absent in the mature mitochondrial isoform. (PMID:17056637)
• Three residues (R116, Y173, R267) that correspond to amino acids known to compose the active site of TruA, a bacterial Psi synthase that is homologous to Pus1p, were mutated in human Pus1p. (PMID:18648068)
• We identified one novel homozygous null mutation in a familial case. It predicts a nonsense mutation at glutamine 154 (Q154X) that would lead to a protein lacking the 266 C-terminal amino acids (PMID:19731322)
• Investigation of the sequence and structural requirements for hPus1p activity on human tRNASer. (PMID:22102571)
• results show that the NTD of ERalpha and AR contains a novel RBM that directly binds SRA, and that STR5 can serve as a novel class of RNA inhibitor of ERalpha and AR signaling by interfering with Pus1p-mediated SRA pseudouridylation (PMID:22998747)
• These results demonstrate a structure-dependent mode of mRNA target recognition by a conserved pseudouridine synthase and implicate modulation of RNA structure as the probable mechanism to regulate mRNA pseudouridylation. (PMID:31477916)
• Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing. (PMID:35051350)
• Pseudouridine synthase 1 promotes hepatocellular carcinoma through mRNA pseudouridylation to enhance the translation of oncogenic mRNAs. (PMID:38015993)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pus1	ENSDARG00000045562
mus_musculus	Pus1	ENSMUSG00000029507
rattus_norvegicus	Pus1	ENSRNOG00000037500
drosophila_melanogaster	Pus1	FBGN0038811
caenorhabditis_elegans		WBGENE00004248

Paralogs (2): PUS3 (ENSG00000110060), PUSL1 (ENSG00000169972)

Protein

Protein identifiers

Pseudouridylate synthase 1 homolog — Q9Y606 (reviewed: Q9Y606)

Alternative names: tRNA pseudouridine synthase 1, tRNA pseudouridine(38-40) synthase, tRNA pseudouridylate synthase I, tRNA-uridine isomerase I

All UniProt accessions (10): E5KMT5, E5KMT6, Q9Y606, F5GXL3, F5GY32, F5H168, F5H1B2, F5H1S9, F8W9U5, G8JLB3

UniProt curated annotations — full annotation on UniProt →

Function. Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs. Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA. Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5’-UGUAG-3’. Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions. Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3’-end processing. Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 mRNA.

Subunit / interactions. Monomer. Forms a complex with RARG and the SRA1 RNA in the nucleus.

Subcellular location. Mitochondrion Nucleus. Cytoplasm.

Tissue specificity. Widely expressed. High levels of expression found in brain and skeletal muscle.

Disease relevance. Myopathy with lactic acidosis and sideroblastic anemia 1 (MLASA1) [MIM:600462] A rare oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Affected individuals manifest progressive muscle weakness, exercise intolerance, lactic acidosis, sideroblastic anemia and delayed growth. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the tRNA pseudouridine synthase TruA family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y606-1	1	yes
Q9Y606-2	2

RefSeq proteins (3): NP_001002019, NP_001002020, NP_079491* (*=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
IPR041708	PUS1/PUS2-like	Family

Pfam: PF01416

Enzyme classification (BRENDA):

• EC 5.4.99.B22 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 3 shown:

• uridine(38/39/40) in tRNA = pseudouridine(38/39/40) in tRNA (RHEA:22376)
• a uridine in tRNA = a pseudouridine in tRNA (RHEA:54572)
• a uridine in mRNA = a pseudouridine in mRNA (RHEA:56644)

UniProt features (52 total): helix 18, strand 14, sequence variant 7, modified residue 3, region of interest 2, transit peptide 1, chain 1, mutagenesis site 1, sequence conflict 1, turn 1, compositionally biased region 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4J37	X-RAY DIFFRACTION	1.75
4IQM	X-RAY DIFFRACTION	1.8
4ITS	X-RAY DIFFRACTION	1.85
4NZ6	X-RAY DIFFRACTION	2
4NZ7	X-RAY DIFFRACTION	2.7
9H51	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y606-F1	81.80	0.69

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): 146 (nucleophile)

Post-translational modifications (3): 415, 420, 426

Mutagenesis-validated functional residues (1):

Position	Phenotype
146	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol
R-HSA-6787450	tRNA modification in the mitochondrion

MSigDB gene sets: 268 (showing top): ELVIDGE_HYPOXIA_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MRNA_MODIFICATION, GOBP_PSEUDOURIDINE_SYNTHESIS, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RNA_MODIFICATION, MYCMAX_01, MARTIN_VIRAL_GPCR_SIGNALING_UP, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_RNA_SPLICING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, MARZEC_IL2_SIGNALING_UP, DODD_NASOPHARYNGEAL_CARCINOMA_UP, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP

GO Biological Process (9): mRNA processing (GO:0006397), RNA splicing (GO:0008380), tRNA pseudouridine synthesis (GO:0031119), positive regulation of transcription by RNA polymerase II (GO:0045944), mitochondrial tRNA pseudouridine synthesis (GO:0070902), mRNA pseudouridine synthesis (GO:1990481), pseudouridine synthesis (GO:0001522), tRNA processing (GO:0008033), RNA modification (GO:0009451)

GO Molecular Function (10): tRNA binding (GO:0000049), steroid receptor RNA activator RNA binding (GO:0002153), chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), pseudouridine synthase activity (GO:0009982), tRNA pseudouridine(38-40) synthase activity (GO:0160147), mitochondrial tRNA pseudouridine(27/28) synthase activity (GO:0160153), isomerase activity (GO:0016853), tRNA pseudouridine synthase activity (GO:0106029)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
tRNA processing	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	3
pseudouridine synthesis	2
positive regulation of DNA-templated transcription	2
mitochondrion	2
tRNA pseudouridine synthase activity	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cellular anatomical structure	2
mRNA metabolic process	1
tRNA modification	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
tRNA pseudouridine synthesis	1
mitochondrial tRNA modification	1
mRNA modification	1
RNA modification	1
tRNA metabolic process	1
RNA metabolic process	1
macromolecule modification	1
RNA binding	1
single-stranded RNA binding	1
binding	1
transcription coregulator activity	1
nucleic acid binding	1
intramolecular transferase activity	1
catalytic activity	1
pseudouridine synthase activity	1
catalytic activity, acting on a tRNA	1
protein-containing complex	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

2458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PUS1	YARS2	Q9Y2Z4	942
PUS1	DKC1	O60832	911
PUS1	PUS7	Q96PZ0	879
PUS1	TRUB1	Q8WWH5	876
PUS1	TIMM10	P62072	830
PUS1	PUS10	Q3MIT2	810
PUS1	RPUSD2	Q8IZ73	806
PUS1	PUS7L	Q9H0K6	771
PUS1	RPUSD4	Q96CM3	757
PUS1	TRUB2	O95900	751
PUS1	RPUSD3	Q6P087	744
PUS1	RPUSD1	Q9UJJ7	724
PUS1	MTO1	Q9Y2Z2	722
PUS1	TRMU	O75648	718
PUS1	TRIT1	Q9H3H1	701

IntAct

61 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
PPM1G	COPE	psi-mi:“MI:0914”(association)	0.530
NDUFV2	NDUFS8	psi-mi:“MI:0914”(association)	0.530
TRPV5	ATF1	psi-mi:“MI:0914”(association)	0.530
THUMPD1	YBX1	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350
MRPL12		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	GTPBP10	psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
ZNF664	GAPDHS	psi-mi:“MI:0914”(association)	0.350
OXLD1	PRORP	psi-mi:“MI:0914”(association)	0.350
	KIF2A	psi-mi:“MI:0914”(association)	0.350
HES4	CTSV	psi-mi:“MI:0914”(association)	0.350
THUMPD3	TRMU	psi-mi:“MI:0914”(association)	0.350
FRAT2	GSK3A	psi-mi:“MI:0914”(association)	0.350
KLF5	GSK3A	psi-mi:“MI:0914”(association)	0.350
NUP133	GSK3A	psi-mi:“MI:0914”(association)	0.350
PARP8	GSK3A	psi-mi:“MI:0914”(association)	0.350
ABCD4	FCGRT	psi-mi:“MI:0914”(association)	0.350
KIF3A	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL42	UBA6	psi-mi:“MI:0914”(association)	0.350
MRM2	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (169): PUS1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Co-fractionation), PUS1 (Proximity Label-MS), PUS1 (Affinity Capture-MS), PUS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6LAG9, A2RTX5, A6QLY4, A6QNM8, A7M7B9, A9S0B8, A9VB27, B9DFZ0, C1BM18, E2RDZ6, F4JCQ3, G3X8U3, O35980, O70157, O75879, P13051, P36776, P54137, P78549, P97931, Q09907, Q0V9S0, Q13472, Q2KID2, Q4KM92, Q4R380, Q59HJ6, Q5ZKD7, Q640B4, Q7SXA9, Q80UN9, Q80VY9, Q8BLY2, Q8BYM8, Q8CGK3, Q8K582, Q8R5G2, Q8SRB8, Q924S5, Q99JT1

Diamond homologs: A1QYG5, A2SU30, A3CXX4, A5ULI2, A6LDA7, A6T009, B2S1K1, B3EIU9, B3R022, B4SA76, B4U9D9, B5RLM0, B5RQJ5, B5YDX5, B6YQE4, B6YTJ2, B7J0V1, B8E1G5, B8GFU5, C5A7E9, C5D3U9, O26928, O28544, O58941, O66953, O74451, O94295, O94396, P53167, P60351, P70830, Q0SPF2, Q12211, Q2NHB4, Q2NIY3, Q46CU8, Q4KM92, Q50291, Q59S63, Q5LGZ6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 82 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Complex I biogenesis	6	16.8×	6e-04
Mitochondrial ribosome-associated quality control	6	12.5×	2e-03
Respiratory electron transport	6	9.7×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	6	77.2×	4e-08
mitochondrial electron transport, NADH to ubiquinone	5	23.3×	6e-04
proton motive force-driven mitochondrial ATP synthesis	5	17.1×	2e-03
aerobic respiration	5	16.1×	2e-03
mitochondrial translation	5	11.3×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	29
Uncertain significance	156
Likely benign	307
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1361128	NM_025215.6(PUS1):c.10C>T (p.Gln4Ter)	Pathogenic
1427301	NC_000012.11:g.(?132423708)(132423830_?)del	Pathogenic
1445539	NM_025215.6(PUS1):c.929_930del (p.Pro310fs)	Pathogenic
2046890	NM_025215.6(PUS1):c.450dup (p.Ala151fs)	Pathogenic
2129213	NM_025215.6(PUS1):c.790del (p.Leu264fs)	Pathogenic
2137450	NM_025215.6(PUS1):c.460C>T (p.Gln154Ter)	Pathogenic
2537	NM_025215.6(PUS1):c.658G>T (p.Glu220Ter)	Pathogenic
2699263	NM_025215.6(PUS1):c.953G>A (p.Trp318Ter)	Pathogenic
2740250	NM_025215.6(PUS1):c.194del (p.Pro65fs)	Pathogenic
2760800	NM_025215.6(PUS1):c.498dup (p.Leu167fs)	Pathogenic
2762282	NM_025215.6(PUS1):c.581_585del (p.Asn194fs)	Pathogenic
2764056	NM_025215.6(PUS1):c.850del (p.Arg283_Val284insTer)	Pathogenic
2770739	NM_025215.6(PUS1):c.707dup (p.Ala237fs)	Pathogenic
2788808	NM_025215.6(PUS1):c.930del (p.Glu311fs)	Pathogenic
2797131	NM_025215.6(PUS1):c.58G>T (p.Gly20Ter)	Pathogenic
2817103	NM_025215.6(PUS1):c.510del (p.Asn171fs)	Pathogenic
2854983	NM_025215.6(PUS1):c.717C>G (p.Tyr239Ter)	Pathogenic
691962	NM_025215.6(PUS1):c.1122C>G (p.Tyr374Ter)	Pathogenic
830734	NC_000012.12:g.(?131929713)(131943596_?)del	Pathogenic
838402	NM_025215.6(PUS1):c.963_964del (p.Lys322fs)	Pathogenic
840012	NM_025215.6(PUS1):c.801C>G (p.Tyr267Ter)	Pathogenic
844870	NM_025215.6(PUS1):c.225_226delinsTT (p.Glu75_Glu76delinsAspTer)	Pathogenic
852107	NM_025215.6(PUS1):c.722del (p.Gly241fs)	Pathogenic
957639	NM_025215.6(PUS1):c.531_532del (p.Ile178fs)	Pathogenic
1485081	NM_025215.6(PUS1):c.545-2A>G	Likely pathogenic
1503401	NM_025215.6(PUS1):c.304-2A>G	Likely pathogenic
1525331	NC_000012.11:g.(?132416710)(132416867_?)del	Likely pathogenic
2011327	NM_025215.6(PUS1):c.74+2del	Likely pathogenic
221982	NM_025215.6(PUS1):c.883C>T (p.Arg295Trp)	Likely pathogenic
2678106	NM_025215.6(PUS1):c.442-1G>T	Likely pathogenic

SpliceAI

1512 predictions. Top by Δscore:

Variant	Effect	Δscore
12:131929357:A:T	donor_gain	1.0000
12:131929395:G:GT	donor_gain	1.0000
12:131930084:G:GT	donor_gain	1.0000
12:131932173:A:AG	acceptor_gain	1.0000
12:131932173:AGAG:A	acceptor_gain	1.0000
12:131932174:G:GT	acceptor_gain	1.0000
12:131932174:GA:G	acceptor_gain	1.0000
12:131932174:GAGG:G	acceptor_gain	1.0000
12:131932174:GAGGA:G	acceptor_gain	1.0000
12:131932310:AAG:A	donor_loss	1.0000
12:131932311:AG:A	donor_loss	1.0000
12:131932312:GG:G	donor_loss	1.0000
12:131932313:G:T	donor_loss	1.0000
12:131932314:T:G	donor_loss	1.0000
12:131939172:GGGT:G	acceptor_gain	1.0000
12:131939274:GG:G	donor_gain	1.0000
12:131939274:GGGT:G	donor_loss	1.0000
12:131939275:GG:G	donor_gain	1.0000
12:131939276:G:GA	donor_loss	1.0000
12:131939276:G:GG	donor_gain	1.0000
12:131939277:T:A	donor_loss	1.0000
12:131929356:G:GT	donor_gain	0.9900
12:131929378:G:GT	donor_gain	0.9900
12:131929395:G:T	donor_gain	0.9900
12:131930114:C:T	donor_gain	0.9900
12:131930150:G:T	donor_gain	0.9900
12:131939170:CAGG:C	acceptor_loss	0.9900
12:131939171:A:AG	acceptor_gain	0.9900
12:131939171:AG:A	acceptor_gain	0.9900
12:131939171:AGG:A	acceptor_gain	0.9900

AlphaMissense

2793 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:131930113:G:A	G94D	0.998
12:131932308:A:C	D146A	0.998
12:131932308:A:T	D146V	0.998
12:131941315:T:C	F190L	0.998
12:131941317:T:A	F190L	0.998
12:131941317:T:G	F190L	0.998
12:131941612:T:C	F289L	0.998
12:131941614:C:A	F289L	0.998
12:131941614:C:G	F289L	0.998
12:131932307:G:C	D146H	0.997
12:131939200:T:C	S157P	0.997
12:131941334:G:A	C196Y	0.997
12:131941335:T:G	C196W	0.997
12:131941609:A:C	S288R	0.997
12:131941611:C:A	S288R	0.997
12:131941611:C:G	S288R	0.997
12:131941745:T:C	L333P	0.997
12:131930128:G:A	G99D	0.996
12:131932308:A:G	D146G	0.996
12:131932309:C:A	D146E	0.996
12:131932309:C:G	D146E	0.996
12:131939183:C:A	A151E	0.996
12:131939252:T:C	L174P	0.996
12:131941316:T:C	F190S	0.996
12:131941343:G:C	R199T	0.996
12:131941528:C:A	R261S	0.996
12:131941603:G:C	G286R	0.996
12:131941915:T:A	W390R	0.996
12:131941915:T:C	W390R	0.996
12:131932299:C:A	A143D	0.995

dbSNP variants (sampled 300 via entrez): RS1000114146 (12:131937225 C>T), RS1000145772 (12:131933126 A>G), RS1000333669 (12:131936988 C>A,G), RS1000522593 (12:131942812 C>A), RS1000633359 (12:131945140 C>T), RS1000642520 (12:131938984 A>C), RS1000829547 (12:131927661 C>A), RS1000940525 (12:131935798 G>A,T), RS1001000878 (12:131936292 G>A), RS1001001606 (12:131930907 C>T), RS1001096539 (12:131931245 G>A), RS1001130554 (12:131945339 G>A), RS1001394246 (12:131935986 G>A), RS1001469883 (12:131942754 T>C), RS1001477267 (12:131928415 G>C)

Disease associations

OMIM: gene MIM:608109 | disease phenotypes: MIM:600462, MIM:252160

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, lactic acidosis, and sideroblastic anemia 1	Definitive	Autosomal recessive
myopathy, lactic acidosis, and sideroblastic anemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (6): myopathy, lactic acidosis, and sideroblastic anemia (MONDO:0000863), myopathy, lactic acidosis, and sideroblastic anemia 1 (MONDO:0024553), mitochondrial disease (MONDO:0044970), inborn mitochondrial myopathy (MONDO:0009637), sideroblastic anemia (MONDO:0015194), sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1 (MONDO:0009644)

Orphanet (6): Mitochondrial myopathy and sideroblastic anemia (Orphanet:2598), Mitochondrial disease (Orphanet:68380), Sideroblastic anemia (Orphanet:1047), Mitochondrial myopathy (Orphanet:206966), Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B (Orphanet:308393), Encephalopathy due to sulfite oxidase deficiency (Orphanet:833)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000457	Depressed nasal ridge
HP:0000501	Glaucoma
HP:0000580	Pigmentary retinopathy
HP:0000823	Delayed puberty
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001931	Hypochromic anemia
HP:0001935	Microcytic anemia
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002091	Restrictive ventilatory defect
HP:0002151	Increased circulating lactate concentration
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0003128	Lactic acidosis
HP:0003196	Short nose
HP:0003198	Myopathy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005951_3	Body mass index	6.000000e-09
GCST012489_160	Heel bone mineral density x serum urate levels interaction	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000756	Anemia, Sideroblastic	C15.378.050.419; C15.378.190.625.070
D017240	Mitochondrial Myopathies	C05.651.460; C10.668.491.500; C18.452.660.560
C565373	Molybdenum Cofactor Deficiency, Complementation Group B (supp.)
C536101	Myopathy with lactic acidosis and sideroblastic anemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725156 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
Estradiol	increases expression	3
Arsenic	increases expression, affects methylation, affects cotreatment, increases abundance	2
Rotenone	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
trichostatin A	affects expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	affects expression	1
picoxystrobin	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697516	Binding	Inhibition of PUS1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3FE	Abcam HEK293T PUS1 KO	Transformed cell line	Female
CVCL_B7Z3	Abcam Raji PUS1 KO	Cancer cell line	Male
CVCL_B9ZU	Abcam THP-1 PUS1 KO	Cancer cell line	Male
CVCL_C7BI	Abcam PC-3 PUS1 KO	Cancer cell line	Male
CVCL_E0MC	Ubigene HeLa PUS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT03829657	PHASE3	TERMINATED	Phase 3 Clinical Effect Durability of TD-9855 for Treating Symptomatic nOH in Subjects With Primary Autonomic Failure
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT03323749	PHASE3	TERMINATED	A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension
NCT07465198	PHASE2	NOT_YET_RECRUITING	Autologous Stem Cell Therapy in Patients With Multiple System Atrophy
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00457314	PHASE2	UNKNOWN	The Effects of Exercise Versus Inactivity on People With Mitochondrial Muscle Disease
NCT02255422	PHASE2	COMPLETED	RTA 408 Capsules in Patients With Mitochondrial Myopathy - MOTOR
NCT04535609	PHASE2	COMPLETED	An Efficacy and Safety Study of 24 Week Treatment With Mavodelpar (REN001) in Primary Mitochondrial Myopathy Patients
NCT04641962	PHASE2	TERMINATED	A Study to Evaluate ASP0367 in Participants With Primary Mitochondrial Myopathy
NCT05590468	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Vitamin B3 Derivative to Treat Mitochondrial Myopathy
NCT05962333	PHASE2	UNKNOWN	Effect and Safety MABs Administration m.3243A>G Mutation Carriers
NCT06754098	PHASE2	RECRUITING	Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement