PUF60

Summary

PUF60 (poly(U) binding splicing factor 60, HGNC:17042) is a protein-coding gene on chromosome 8q24.3, encoding Poly(U)-binding-splicing factor PUF60 (Q9UHX1). DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 22827 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 278 total — 51 pathogenic, 45 likely-pathogenic
• Phenotypes (HPO): 168
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_078480

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17042
Approved symbol	PUF60
Name	poly(U) binding splicing factor 60
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	FIR, SIAHBP1, RoBPI
Ensembl gene	ENSG00000179950
Ensembl biotype	protein_coding
OMIM	604819
Entrez	22827

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 37 protein_coding, 7 protein_coding_CDS_not_defined, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000313352, ENST00000349157, ENST00000453551, ENST00000456095, ENST00000524570, ENST00000526151, ENST00000526459, ENST00000526683, ENST00000527197, ENST00000527584, ENST00000527744, ENST00000528320, ENST00000528999, ENST00000529999, ENST00000531897, ENST00000531951, ENST00000531995, ENST00000532127, ENST00000532884, ENST00000533162, ENST00000533362, ENST00000703744, ENST00000703803, ENST00000703846, ENST00000703847, ENST00000703848, ENST00000703849, ENST00000703850, ENST00000703851, ENST00000703852, ENST00000703853, ENST00000703866, ENST00000897212, ENST00000897213, ENST00000897214, ENST00000897215, ENST00000897216, ENST00000897217, ENST00000897218, ENST00000934070, ENST00000934071, ENST00000934072, ENST00000934073, ENST00000934074, ENST00000934075, ENST00000963444, ENST00000963445, ENST00000963446, ENST00000963447, ENST00000963448

RefSeq mRNA: 11 — MANE Select: NM_078480 NM_001136033, NM_001271096, NM_001271097, NM_001271098, NM_001271099, NM_001271100, NM_001362895, NM_001362896, NM_001362897, NM_014281, NM_078480

CCDS: CCDS47933, CCDS47934, CCDS47935, CCDS59514, CCDS59515, CCDS59516, CCDS94354, CCDS94355, CCDS94356

Canonical transcript exons

ENST00000526683 — 12 exons

Exon	Start	End
ENSE00002187873	143829280	143829315
ENSE00002192916	143816344	143816819
ENSE00002462385	143816910	143817145
ENSE00003482407	143821818	143821913
ENSE00003485633	143817331	143817466
ENSE00003525377	143824313	143824399
ENSE00003535252	143821597	143821686
ENSE00003553773	143817862	143818075
ENSE00003573444	143818373	143818534
ENSE00003648872	143817592	143817782
ENSE00003668241	143818193	143818285
ENSE00003672554	143820666	143820716

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 98.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.0805 / max 202.9425, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95538	51.7746	1822
95539	4.9309	1633
95537	0.9375	672
95536	0.4375	130

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.21	gold quality
right uterine tube	UBERON:0001302	97.76	gold quality
ganglionic eminence	UBERON:0004023	97.61	gold quality
embryo	UBERON:0000922	97.60	gold quality
peripheral nervous system	UBERON:0000010	97.59	gold quality
nerve	UBERON:0001021	97.59	gold quality
tibial nerve	UBERON:0001323	97.59	gold quality
prefrontal cortex	UBERON:0000451	97.53	gold quality
fallopian tube	UBERON:0003889	97.45	gold quality
substantia nigra	UBERON:0002038	97.36	gold quality
frontal cortex	UBERON:0001870	97.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.30	gold quality
skin of leg	UBERON:0001511	97.26	gold quality
apex of heart	UBERON:0002098	97.25	gold quality
putamen	UBERON:0001874	97.23	gold quality
right frontal lobe	UBERON:0002810	97.20	gold quality
skin of abdomen	UBERON:0001416	97.18	gold quality
Ammon’s horn	UBERON:0001954	97.17	gold quality
zone of skin	UBERON:0000014	97.16	gold quality
caudate nucleus	UBERON:0001873	97.15	gold quality
cerebral cortex	UBERON:0000956	97.10	gold quality
temporal lobe	UBERON:0001871	97.09	gold quality
amygdala	UBERON:0001876	97.06	gold quality
left uterine tube	UBERON:0001303	97.05	gold quality
nucleus accumbens	UBERON:0001882	97.04	gold quality
hypothalamus	UBERON:0001898	97.02	gold quality
anterior cingulate cortex	UBERON:0009835	97.00	gold quality
mucosa of transverse colon	UBERON:0004991	96.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.93	gold quality
lower esophagus	UBERON:0013473	96.92	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-100618	no	198.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NFKB

miRNA regulators (miRDB)

19 targeting PUF60, 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-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-34C-3P	98.11	65.60	858
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-3918	96.13	64.65	1300

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 28)

• Results describe the roles of the FarUpStream Element (FUSE), FUSE Binding Protein (FBP), FBP Interacting Repressor (FIR), and TFIIH in the regulation of c-myc expression. (PMID:16628215)
• study identified PUF60 as a factor that promotes splicing of an intron with a weak 3’ splice-site; demonstrated that PUF60 can functionally substitute for U2AF(65)in vitro, but splicing is strongly stimulated by the presence of both proteins (PMID:17579712)
• Puf60-UHM binds to ULM sequences in the splicing factors SF1, U2AF65, and SF3b155. (PMID:18974054)
• FIR is monomeric in solution but dimerizes upon DNA binding; DNA-induced dimerization is mediated by FIR’s RNA recognition motif. (PMID:20420426)
• Data indicate that altered FIR and c-myc pre-mRNA splicing, in addition to c-Myc expression by augmented FIR/FIRDeltaexon2-SAP155 complex, potentially contribute to colorectal cancer development. (PMID:22496461)
• Circulating FIR variant mRNA in the peripheral blood of cancer patients were significantly overexpressed compared to that in healthy volunteers. (PMID:23113893)
• The interaction between SAP155 and FIR/FIRDeltaexon2 not only integrates cell-cycle progression and c-Myc transcription by modifying P27 and P89 expression. (PMID:23594796)
• Haploinsufficiency of each of SCRIB or PUF60 contribute uniquely to specific endophenotypes (e.g., coloboma, heart defects), and binary interaction potentially exacerbates other aspects of the clinical pathology of individuals with 8q24.3 deletion. (PMID:24140112)
• High FBP-interacting repressor expression is associated with hepatocellular carcinoma. (PMID:24811221)
• Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. (PMID:24824848)
• Concomitant over expression of far upstream element (FUSE) binding protein (FBP) interacting repressor (FIR) and its splice variants induce migration and invasion of non-small cell lung cancer cells. (PMID:26177862)
• Mutations in PUF60 gene is associated with idiopathic hypereosinophilic syndrome. (PMID:26497854)
• PUF60 auto-antibodies are detected in the sera of early-stage colon cancer patients and level decreases after surgery. (PMID:27756887)
• These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion (PMID:27804958)
• 3 Verheij syndrome patients with de novo pathogenic variants in PUF60 are described. Mutations in gene PUF60 were analyzed. (PMID:28074499)
• Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies. (PMID:28327570)
• The present report describes a de novo missense mutation in PUF60, detected in a boy with multiple congenital anomalies. (PMID:28471317)
• Authors report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. A two base pair deletion was identified in the PUF60 gene. Result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. (PMID:28990276)
• PUF60 is involved in: 1) up-regulation of core promoter activity through its interaction with transcription factor TCF7L2, 2) promotion of 3.5 kb RNA degradation and 3) suppression of 3.5 kb RNA splicing. (PMID:28993636)
• Anti-PUF60 antibodies were nonspecific for myositis, since they could be detected in other rheumatic diseases. (PMID:29541951)
• PUF60-activated exons uncover altered 3’ splice-site selection by germline missense mutations in a single RNA recognition motif. (PMID:29788428)
• Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase. (PMID:33061812)
• Unraveling the mechanism of recognition of the 3’ splice site of the adenovirus major late promoter intron by the alternative splicing factor PUF60. (PMID:33253191)
• PUF60 promotes glioblastoma progression through regulation of EGFR stability. (PMID:36335869)
• The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome. (PMID:36367278)
• PUF60-related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic PUF60 variants. (PMID:37303278)
• PUF60 promotes cell cycle and lung cancer progression by regulating alternative splicing of CDC25C. (PMID:37682709)
• Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders. (PMID:38396730)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	puf60b	ENSDARG00000001241
danio_rerio	puf60a	ENSDARG00000032175
mus_musculus	Puf60	ENSMUSG00000002524
rattus_norvegicus	Puf60	ENSRNOG00000009960
drosophila_melanogaster	hfp	FBGN0028577
caenorhabditis_elegans	rnp-6	WBGENE00004389

Paralogs (24): ELAVL1 (ENSG00000066044), PABPC1 (ENSG00000070756), RBMS2 (ENSG00000076067), PABPC4 (ENSG00000090621), PABPC1L (ENSG00000101104), ELAVL2 (ENSG00000107105), RBM24 (ENSG00000112183), TARDBP (ENSG00000120948), HNRNPR (ENSG00000125944), RBM38 (ENSG00000132819), SYNCRIP (ENSG00000135316), SF3B4 (ENSG00000143368), RBMS3 (ENSG00000144642), PABPC3 (ENSG00000151846), RBMS1 (ENSG00000153250), RBM45 (ENSG00000155636), ELAVL4 (ENSG00000162374), PABPC5 (ENSG00000174740), PABPC1L2B (ENSG00000184388), PABPC1L2A (ENSG00000186288), RBM34 (ENSG00000188739), ELAVL3 (ENSG00000196361), RBM14 (ENSG00000239306), PABPC4L (ENSG00000254535)

Protein

Protein identifiers

Poly(U)-binding-splicing factor PUF60 — Q9UHX1 (reviewed: Q9UHX1)

Alternative names: 60 kDa poly(U)-binding-splicing factor, FUSE-binding protein-interacting repressor, Ro-binding protein 1, Siah-binding protein 1

All UniProt accessions (10): A0A994J4J5, A0A994J6K6, A0A994J6L7, Q9UHX1, E9PL19, E9PMU7, E9PN18, E9PQ56, H0YCP8, H0YEM1

UniProt curated annotations — full annotation on UniProt →

Function. DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3’-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3’-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with RO60. Binds to poly(U) RNA.

Subunit / interactions. Homodimer. Associates with the spliceosome. Found in a complex with RO60 and Y5 RNA. Found in a complex with FUBP1 and far upstream element (FUSE) DNA segment. Interacts directly with ERCC3. Interacts with CDK7 and GTF2H1. Interacts with SRSF11/P54. Does not interact with ERCC3 in xeroderma pigmentosum complementation group B (XPB) cells. Interacts with ARGLU1; interaction may be involved in ARGLU1-mediated modulation of alternative splicing.

Subcellular location. Nucleus.

Tissue specificity. Isoform 2 is expressed in colonic epithelium and colorectal epithelium cancer (at protein level). Isoform 6 is expressed in colorectal epithelial cancer but below detection level in colonic epithelium. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes.

Disease relevance. Verheij syndrome (VRJS) [MIM:615583] A syndrome characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The third RNA recognition motif, called PUMP domain, is atypical and may rather mediate homodimerization and/or protein-protein interactions.

Miscellaneous. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells.

Similarity. Belongs to the RRM half pint family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9UHX1-1	1	yes
Q9UHX1-2	2
Q9UHX1-3	3
Q9UHX1-4	4
Q9UHX1-5	5
Q9UHX1-6	6

RefSeq proteins (11): NP_001129505, NP_001258025, NP_001258026, NP_001258027, NP_001258028, NP_001258029, NP_001349824, NP_001349825, NP_001349826, NP_055096, NP_510965* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR003954	RRM_euk-type	Domain
IPR006532	PUF60-like	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034209	PUF60_RRM1	Domain
IPR034211	PUF60_RRM2	Domain
IPR034212	PUF60_RRM3	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR051974	PUF60_regulator	Family

Pfam: PF00076

UniProt features (63 total): strand 18, helix 15, modified residue 6, cross-link 6, turn 4, domain 3, splice variant 3, region of interest 3, sequence conflict 2, chain 1, sequence variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
3UE2	X-RAY DIFFRACTION	1.23
3US5	X-RAY DIFFRACTION	1.38
7Z3X	X-RAY DIFFRACTION	1.65
5KW6	X-RAY DIFFRACTION	1.91
6SLO	X-RAY DIFFRACTION	1.94
5KVY	X-RAY DIFFRACTION	1.95
6LUR	X-RAY DIFFRACTION	2
7Q8A	X-RAY DIFFRACTION	2.05
2QFJ	X-RAY DIFFRACTION	2.1
5KW1	X-RAY DIFFRACTION	2.1
3DXB	X-RAY DIFFRACTION	2.2
3UWT	X-RAY DIFFRACTION	2.5
5KWQ	X-RAY DIFFRACTION	2.8
2DNY	SOLUTION NMR
2KXF	SOLUTION NMR
2KXH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHX1-F1	69.21	0.24

Functional residue map

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

Post-translational modifications (12): 244, 251, 314, 454, 43, 80, 419, 458, 14, 14, 60, 112

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9943411	CHD1 and CHD2 subfamily

MSigDB gene sets: 522 (showing top): MORF_MTA1, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, MORF_UBE2I, MORF_HDAC1, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, MORF_RAD21, MORF_PSMC2, PATIL_LIVER_CANCER, MORF_SKP1A, MORF_CTBP1, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION

GO Biological Process (6): alternative mRNA splicing, via spliceosome (GO:0000380), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA splice site recognition (GO:0006376), apoptotic process (GO:0006915), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (6): DNA binding (GO:0003677), RNA binding (GO:0003723), identical protein binding (GO:0042802), cadherin binding (GO:0045296), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cell junction (GO:0030054), ribonucleoprotein complex (GO:1990904), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
mRNA Splicing	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
CHD chromatin remodelers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
nucleic acid binding	2
binding	2
cellular anatomical structure	2
mRNA splicing, via spliceosome	1
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
spliceosomal complex assembly	1
protein-RNA complex assembly	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
mRNA metabolic process	1
protein binding	1
cell adhesion molecule binding	1
nuclear lumen	1
protein-containing complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2206 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PUF60	FUBP1	Q96AE4	975
PUF60	HNRNPK	P61978	967
PUF60	FXR2	P51116	958
PUF60	ERCC3	P19447	947
PUF60	FXR1	P51114	928
PUF60	SF3B3	Q15393	910
PUF60	SF3B1	O75533	879
PUF60	IMMT	Q16891	878
PUF60	ERCC2	P18074	796
PUF60	FUBP3	Q96I24	683
PUF60	GTF2H4	Q92759	670
PUF60	MYC	P01106	655
PUF60	U2AF1	Q01081	638
PUF60	PTBP1	P26599	624
PUF60	HNRNPC	P07910	595

IntAct

243 interactions, top by confidence:

A	B	Type	Score
SAP30BP	PUF60	psi-mi:“MI:0915”(physical association)	0.900
PUF60	SAP30BP	psi-mi:“MI:0915”(physical association)	0.900
PUF60	U2AF2	psi-mi:“MI:0915”(physical association)	0.850
SRSF11	PUF60	psi-mi:“MI:0915”(physical association)	0.770
PUF60	SRSF11	psi-mi:“MI:0915”(physical association)	0.770
PUF60	PUF60	psi-mi:“MI:0915”(physical association)	0.750
SIAH1	PUF60	psi-mi:“MI:0915”(physical association)	0.740
PUF60	SIAH1	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BORCS5	PUF60	psi-mi:“MI:0915”(physical association)	0.670
PUF60	MED28	psi-mi:“MI:0915”(physical association)	0.670
MED28	PUF60	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (502): PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), PUF60 (Two-hybrid), KIAA0907 (Two-hybrid), UPF2 (Two-hybrid), SAP30BP (Two-hybrid), QRICH1 (Two-hybrid), MED28 (Two-hybrid), KIAA1683 (Two-hybrid), LOH12CR1 (Two-hybrid)

ESM2 similar proteins: A0A8M1NHK4, A0AV96, B3M3R5, B4KX02, O22173, O43347, P86049, Q05196, Q15233, Q1LZD9, Q32NN2, Q3UEB3, Q4KLH4, Q5R469, Q5R5P4, Q5R9H4, Q5RFL9, Q5W9D5, Q5W9D6, Q5W9D7, Q5YD48, Q61474, Q66H68, Q6DEY7, Q6GR16, Q6IRN2, Q6P0D0, Q7JJZ8, Q8GZ26, Q8K3P4, Q8MSV2, Q8R326, Q8TBY0, Q8WXF1, Q91WT8, Q91XU1, Q920Q6, Q923K9, Q96DH6, Q96PU8

Diamond homologs: A0A8M1NHK4, A0AV96, A0JM51, A4FV72, A4QUF0, A8WLV5, O01671, O04425, O43040, O43390, O60506, P28659, P33240, P86049, Q08BH5, Q08E07, Q0P4R6, Q0V9L3, Q10B98, Q14498, Q28HE9, Q2HJG2, Q2UK72, Q3UEB3, Q4QQT3, Q4R2Z0, Q4R535, Q5B630, Q5EA36, Q5R469, Q5R5P4, Q5R723, Q5R9H4, Q5RC41, Q5RC80, Q5RDA3, Q5SZQ8, Q5YD48, Q66H68, Q6DCB7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PUF60	“form complex”	SCF(TBL1)	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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
Transport of Mature Transcript to Cytoplasm	5	15.9×	9e-04
mRNA Splicing	14	12.8×	8e-10
Processing of Capped Intron-Containing Pre-mRNA	18	12.3×	2e-12
mRNA 3’-end processing	7	11.5×	2e-04
mRNA Polyadenylation	14	10.2×	9e-09
mRNA Splicing - Major Pathway	22	10.0×	2e-13
Transport of Mature mRNA derived from an Intron-Containing Transcript	7	8.9×	9e-04
Dengue Virus-Host Interactions	19	7.2×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mRNA splicing, via spliceosome	5	28.6×	9e-05
negative regulation of mRNA splicing, via spliceosome	5	24.7×	2e-04
spliceosomal complex assembly	6	23.3×	3e-05
RNA splicing, via transesterification reactions	5	20.1×	4e-04
mRNA splicing, via spliceosome	22	13.0×	2e-15
regulation of alternative mRNA splicing, via spliceosome	8	12.6×	4e-05
mRNA transport	7	11.9×	2e-04
mRNA export from nucleus	5	9.5×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	51
Likely pathogenic	45
Uncertain significance	101
Likely benign	39
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1034211	NM_078480.3(PUF60):c.628C>T (p.Gln210Ter)	Pathogenic
1182464	NM_078480.3(PUF60):c.382_383del (p.Met128fs)	Pathogenic
1333184	NM_078480.3(PUF60):c.1154_1166del (p.Pro385fs)	Pathogenic
1333187	NM_078480.3(PUF60):c.860dup (p.Met287fs)	Pathogenic
1334130	NM_078480.3(PUF60):c.672dup (p.Phe225fs)	Pathogenic
1334131	NM_078480.3(PUF60):c.848_849del (p.Ala283fs)	Pathogenic
1402726	NM_078480.3(PUF60):c.714dup (p.Asp239fs)	Pathogenic
1684557	GRCh37/hg19 8q24.3(chr8:144902401-144905800)x1	Pathogenic
1686112	NM_078480.3(PUF60):c.271C>T (p.Gln91Ter)	Pathogenic
1686113	NM_078480.3(PUF60):c.208-1G>A	Pathogenic
1691649	NM_078480.3(PUF60):c.1123C>T (p.Gln375Ter)	Pathogenic
1695240	NM_078480.3(PUF60):c.51del (p.Ser18fs)	Pathogenic
1699420	NM_078480.3(PUF60):c.510+1G>A	Pathogenic
1710261	NM_078480.3(PUF60):c.636_640del (p.Gln212fs)	Pathogenic
1722774	NM_078480.3(PUF60):c.1357C>T (p.Gln453Ter)	Pathogenic
2442364	NM_078480.3(PUF60):c.852_853del (p.Ser285fs)	Pathogenic
2690939	NM_078480.3(PUF60):c.1658A>G (p.Asp553Gly)	Pathogenic
2690940	NM_078480.3(PUF60):c.206del (p.Lys69fs)	Pathogenic
280867	NM_078480.3(PUF60):c.485G>A (p.Trp162Ter)	Pathogenic
3024221	NM_078480.3(PUF60):c.822C>G (p.Tyr274Ter)	Pathogenic
3075702	NM_078480.3(PUF60):c.1006C>T (p.Gln336Ter)	Pathogenic
3255207	NM_078480.3(PUF60):c.615del (p.Ser206fs)	Pathogenic
3572524	NM_078480.3(PUF60):c.634C>T (p.Gln212Ter)	Pathogenic
372883	NM_078480.3(PUF60):c.590dup (p.Arg198fs)	Pathogenic
3777301	NM_078480.3(PUF60):c.388C>T (p.Arg130Cys)	Pathogenic
4071992	NM_078480.3(PUF60):c.510+2T>A	Pathogenic
4085253	NM_078480.3(PUF60):c.894_895dup (p.Val299fs)	Pathogenic
430000	NM_078480.3(PUF60):c.993del (p.Lys332fs)	Pathogenic
4685507	NM_078480.3(PUF60):c.1064_1065insAC (p.Ala357fs)	Pathogenic
4813847	NM_078480.3(PUF60):c.999_1002dup (p.Ala335fs)	Pathogenic

SpliceAI

1844 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143816815:GTAGA:G	acceptor_gain	1.0000
8:143816816:TAGA:T	acceptor_gain	1.0000
8:143816817:AGA:A	acceptor_gain	1.0000
8:143816818:GA:G	acceptor_gain	1.0000
8:143816820:C:CC	acceptor_gain	1.0000
8:143816822:G:C	acceptor_gain	1.0000
8:143816828:C:CT	acceptor_gain	1.0000
8:143816829:A:T	acceptor_gain	1.0000
8:143816834:C:CT	acceptor_gain	1.0000
8:143816835:G:T	acceptor_gain	1.0000
8:143816907:TA:T	donor_loss	1.0000
8:143816908:A:AC	donor_gain	1.0000
8:143816908:ACCT:A	donor_gain	1.0000
8:143816909:C:A	donor_loss	1.0000
8:143816909:C:CC	donor_gain	1.0000
8:143816909:CCT:C	donor_gain	1.0000
8:143816909:CCTC:C	donor_gain	1.0000
8:143816911:T:TA	donor_gain	1.0000
8:143817141:CACAC:C	acceptor_gain	1.0000
8:143817142:ACAC:A	acceptor_gain	1.0000
8:143817143:CAC:C	acceptor_gain	1.0000
8:143817143:CACC:C	acceptor_gain	1.0000
8:143817144:AC:A	acceptor_gain	1.0000
8:143817145:CC:C	acceptor_gain	1.0000
8:143817146:C:CC	acceptor_gain	1.0000
8:143817146:CTG:C	acceptor_loss	1.0000
8:143817149:C:CT	acceptor_gain	1.0000
8:143817150:A:T	acceptor_gain	1.0000
8:143817326:CTCA:C	donor_loss	1.0000
8:143817463:CTTC:C	acceptor_gain	1.0000

AlphaMissense

3645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143816569:G:T	A544D	1.000
8:143816575:A:T	V542E	1.000
8:143816581:C:G	R540P	1.000
8:143816589:A:C	F537L	1.000
8:143816589:A:T	F537L	1.000
8:143816590:A:C	F537C	1.000
8:143816590:A:G	F537S	1.000
8:143816591:A:G	F537L	1.000
8:143816594:A:G	W536R	1.000
8:143816594:A:T	W536R	1.000
8:143816596:C:G	R535P	1.000
8:143816597:G:T	R535S	1.000
8:143816605:A:G	L532P	1.000
8:143816605:A:T	L532H	1.000
8:143816617:G:T	A528D	1.000
8:143816643:A:C	F519L	1.000
8:143816643:A:T	F519L	1.000
8:143816644:A:G	F519S	1.000
8:143816645:A:G	F519L	1.000
8:143816650:A:T	V517E	1.000
8:143816652:A:C	F516L	1.000
8:143816652:A:T	F516L	1.000
8:143816653:A:G	F516S	1.000
8:143816654:A:G	F516L	1.000
8:143816656:A:C	I515S	1.000
8:143816656:A:G	I515T	1.000
8:143816656:A:T	I515N	1.000
8:143816662:A:T	V513D	1.000
8:143816705:A:C	Y499D	1.000
8:143816707:A:T	I498N	1.000

dbSNP variants (sampled 300 via entrez): RS1000042878 (8:143826055 T>C), RS1000429809 (8:143821120 G>A), RS1000441579 (8:143826323 C>T), RS1000477636 (8:143816408 G>A,C), RS1000541986 (8:143829341 C>G,T), RS1000594091 (8:143822258 G>A,C,T), RS1000765919 (8:143826730 GA>G,GAA), RS1000895085 (8:143816321 C>G,T), RS1000931298 (8:143820315 C>A), RS1001045046 (8:143825225 T>C), RS1001111051 (8:143821975 G>C), RS1001135877 (8:143826891 G>A), RS1001551671 (8:143825083 G>A), RS1002047071 (8:143822619 C>G,T), RS1002163574 (8:143817397 G>A,C)

Disease associations

OMIM: gene MIM:604819 | disease phenotypes: MIM:615583, MIM:618603

GenCC curated gene-disease

Disease	Classification	Inheritance
8q24.3 microdeletion syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (6): 8q24.3 microdeletion syndrome (MONDO:0014263), intellectual disability (MONDO:0001071), intellectual disability-cardiac anomalies-short stature-joint laxity syndrome (MONDO:0034989), CHARGE syndrome (MONDO:0008965), syndromic intellectual disability (MONDO:0000508), neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (MONDO:0032829)

Orphanet (5): 8q24.3 microdeletion syndrome (Orphanet:508488), Intellectual disability-cardiac anomalies-short stature-joint laxity syndrome (Orphanet:508498), CHARGE syndrome (Orphanet:138), Rare genetic syndromic intellectual disability (Orphanet:183763), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

168 total (30 of 168 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000085	Horseshoe kidney
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000107	Renal cyst
HP:0000122	Unilateral renal agenesis
HP:0000125	Pelvic kidney
HP:0000175	Cleft palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000300	Oval face
HP:0000303	Mandibular prognathia
HP:0000308	Microretrognathia
HP:0000319	Smooth philtrum
HP:0000321	Square face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058747	CHARGE Syndrome	C09.218.458.341.186.500.250; C10.597.751.418.341.186.500.250; C10.597.751.941.162.625.250; C11.270.147.500; C11.966.075.375.250; C16.131.077.299.250; C16.320.165; C23.888.592.763.393.341.186.500.500; C23.888.592.763.941.162.625.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725159 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.23	Kd	5.834	nM	CHEMBL5653589
8.23	ED50	5.834	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149153: Binding affinity to human PUF60 incubated for 45 mins by Kinobead based pull down assay	kd	0.0058	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Arsenic	increases expression, affects methylation, increases abundance	2
Valproic Acid	affects cotreatment, increases expression, affects expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
2,4,6-tribromophenol	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	decreases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652195	Binding	Binding affinity to human PUF60 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders