HNRNPU

Summary

HNRNPU (heterogeneous nuclear ribonucleoprotein U, HGNC:5048) is a protein-coding gene on chromosome 1q44, encoding Heterogeneous nuclear ribonucleoprotein U (Q00839). DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mitotic cell progression. It is a common-essential gene (DepMap: required in 97.3% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14.

Source: NCBI Gene 3192 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 1,197 total — 106 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 48
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.3% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_031844

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5048
Approved symbol	HNRNPU
Name	heterogeneous nuclear ribonucleoprotein U
Location	1q44
Locus type	gene with protein product
Status	Approved
Aliases	SAF-A, FLJ37978, FLJ30202
Ensembl gene	ENSG00000153187
Ensembl biotype	protein_coding
OMIM	602869
Entrez	3192

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 23 protein_coding, 10 retained_intron, 9 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000283179, ENST00000366525, ENST00000366527, ENST00000440865, ENST00000444376, ENST00000465881, ENST00000468690, ENST00000475997, ENST00000476241, ENST00000483966, ENST00000489705, ENST00000638230, ENST00000638301, ENST00000638475, ENST00000638589, ENST00000638716, ENST00000638952, ENST00000639064, ENST00000639628, ENST00000639667, ENST00000639824, ENST00000639880, ENST00000640001, ENST00000640056, ENST00000640119, ENST00000640218, ENST00000640264, ENST00000640306, ENST00000640440, ENST00000640657, ENST00000649899, ENST00000704074, ENST00000899281, ENST00000919765, ENST00000919766, ENST00000919767, ENST00000919768, ENST00000919769, ENST00000919770, ENST00000919771, ENST00000945103, ENST00000945104, ENST00000945105, ENST00000945106

RefSeq mRNA: 2 — MANE Select: NM_031844 NM_004501, NM_031844

CCDS: CCDS31081, CCDS41479

Canonical transcript exons

ENST00000640218 — 14 exons

Exon	Start	End
ENSE00003505001	244857598	244857717
ENSE00003513208	244855424	244855608
ENSE00003532483	244856728	244856856
ENSE00003539857	244862619	244862730
ENSE00003553497	244856457	244856625
ENSE00003569797	244858729	244858841
ENSE00003600530	244855904	244856158
ENSE00003620997	244862461	244862534
ENSE00003680033	244859275	244859374
ENSE00003683070	244858011	244858274
ENSE00003684268	244860335	244860474
ENSE00003792894	244854973	244855044
ENSE00003801514	244850297	244854503
ENSE00003804577	244863617	244864543

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 296.5383 / max 3636.3683, expressed in 1828 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18413	112.6229	1824
18415	111.0164	1828
18414	48.6044	1824
18399	4.3569	1388
18416	3.6069	1508
18404	3.3911	1026
18397	1.8895	1012
18401	1.6413	853
18411	1.5744	651
18402	1.4291	687

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.76	gold quality
male germ cell	CL:0000015	99.66	gold quality
ventricular zone	UBERON:0003053	99.66	gold quality
ganglionic eminence	UBERON:0004023	99.58	gold quality
embryo	UBERON:0000922	99.54	gold quality
tendon of biceps brachii	UBERON:0008188	99.52	gold quality
cortical plate	UBERON:0005343	99.45	gold quality
caput epididymis	UBERON:0004358	99.32	gold quality
tendon	UBERON:0000043	99.28	gold quality
calcaneal tendon	UBERON:0003701	99.27	gold quality
bronchial epithelial cell	CL:0002328	99.19	gold quality
colonic epithelium	UBERON:0000397	99.19	gold quality
trabecular bone tissue	UBERON:0002483	99.18	gold quality
corpus epididymis	UBERON:0004359	99.16	gold quality
mammary duct	UBERON:0001765	99.15	gold quality
cauda epididymis	UBERON:0004360	99.15	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.15	gold quality
sural nerve	UBERON:0015488	99.08	gold quality
endometrium	UBERON:0001295	99.03	gold quality
left ovary	UBERON:0002119	99.02	gold quality
corpus callosum	UBERON:0002336	99.02	gold quality
superficial temporal artery	UBERON:0001614	99.01	gold quality
lower lobe of lung	UBERON:0008949	99.01	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.00	gold quality
seminal vesicle	UBERON:0000998	98.99	gold quality
right ovary	UBERON:0002118	98.99	gold quality
right testis	UBERON:0004534	98.98	gold quality
ovary	UBERON:0000992	98.97	gold quality
tonsil	UBERON:0002372	98.97	gold quality
medial globus pallidus	UBERON:0002477	98.96	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	14.23
E-MTAB-6911	no	1314.29
E-GEOD-93593	no	6.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MAX

miRNA regulators (miRDB)

207 targeting HNRNPU, 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-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4650-5P	99.98	64.69	999
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-433-3P	99.98	69.37	1203

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 97.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• hnRNP-U engages a highly neddlylated active SCF beta-TRCP which dissociates in the presence of a high-affinity substrate, resulting in the ubiquitination of the latter. (PMID:11850407)
• Scaffold/matrix attachment region elements interact with a p300-scaffold attachment factor A complex and are bound by acetylated nucleosomes. (PMID:11909954)
• Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription (PMID:15096513)
• PRMT1 has a role in arginine methylation of SAF-A (PMID:15364944)
• The results suggest that HIV-1 requires machinery for the nuclear export of viral mRNAs that can be specifically blocked by an interfering gene. (PMID:16916646)
• These findings increase our knowledge of how WT1 exerts its transcriptional regulatory role and suggests that hnRNP-U may be a candidate Wilms’ tumour gene at 1q44. (PMID:16924231)
• the spatial proximities among a constellation of functionally related sites that are found within euchromatic regions of the cell nucleus including: HP1gamma, RNA polymerase II, matrin 3, and SAF-A sites (PMID:18618731)
• The histone acetyltransferase (HAT) PCAF associates with actin and hnRNP U. (PMID:18710935)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• hnRNP-U is phosphorylated at Ser59 by DNA-PK in vitro and in cells in response to DNA double-strand breaks. (PMID:19351595)
• Data demonstrate that hnRNP U is involved in HP1alpha function, shedding new light on the mode of action of HP1alpha and on the function of hnRNP U. (PMID:19617346)
• Data demonstrate that expression levels of hnRNP A1, Q, K, R, and U influence HIV-1 production by persistently infected astrocytes, linking these hnRNPs to HIV replication. (PMID:19808671)
• Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. (PMID:20150277)
• Single nucleotide polymorphism in HNRPU gene is associated with speech delay, seizures and variable corpus callosum thickness. (PMID:20382278)
• hnRNP U/SAF-A/SP120 regulates the enzyme DNA Topoisomerase IIbeta in dual ways (PMID:20554522)
• The nuclear scaffold protein (SAF-A) is a novel spindle regulator that plays an essential role in kinetochore-microtubules (MT)attachment and mitotic spindle organization. (PMID:21242313)
• SAF-A interacts with BRG1 and both components are required for RNA Polymerase II Mediated Transcription (PMID:22162999)
• hnRNP U is a regulator of SMN2 splicing. (PMID:22325991)
• The results suggest that NCRNA00201 is not a major gene for microcephaly and corpus callosum abnormalities but is a good candidate for intellectual disability and seizures. (PMID:22678713)
• These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for intellectual disability (ID) and seizures. (PMID:22678713)
• experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system against viruses (PMID:22810585)
• the hnRNP-U protection of cells after oxidative stress is largely due to enhancement of NEIL1-mediated repair. (PMID:22902625)
• Induction of caspase-9b expression is due to activation of hnRNP L via phosphorylation to compete/inhibit hnRNP U association with exon 3 of Casp9 mRNA. (PMID:23396972)
• demonstrate that H19 inhibits RNA Pol II-mediated transcription by disrupting the hnRNP U-actin complex (PMID:23811339)
• Nuclear TDP-43 becomes neurotoxic by escaping from the inhibitory regulation by hnRNP-U or hnRNP-A2. hnRNP-U inhibits TDP-43-mediated alterations in splicing of POLDIP3 mRNA. (PMID:25378556)
• both phosphorylation and dephosphorylation of SAF-A serine 59 by PLK1 and PP2A, respectively, are required for accurate and timely exit from mitosis. (PMID:25986610)
• CENP-W interacts with hnRNPU and may contribute to kinetochore-microtubule attachment in mitotic cells. (PMID:26881882)
• mutual regulatory mechanisms exist between PP4 and SAF-A. Interactions between PP4 and SAF-A played a role in prometaphase/metaphase transition. (PMID:27041735)
• SAF-A, in concert with Ku, temporally regulates base damage repair in irradiated cell genome. (PMID:27303920)
• results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans (PMID:28283832)
• We broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe intellectual disability with striking speech impairment and variable central nervous system, cardiac, and renal anomalies. (PMID:28393272)
• Results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability. (PMID:28622508)
• HNRPU deletion is associated with neurodevelopmental disorders. (PMID:28815871)
• This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency (PMID:28944577)
• It aims to discuss the role of HNRNPU in maintaining the 3D chromatin architecture, as well as the recent development and human diseases involved in this nuclear matrix (NM)-associated protein. (PMID:29981443)
• HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. (PMID:31311954)
• our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing (PMID:31331910)
• Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review. (PMID:32319732)
• The splicing regulatory factor hnRNPU is a novel transcriptional target of c-Myc in hepatocellular carcinoma. (PMID:33040326)
• De novo frameshift variants of HNRNPU in patients with early infantile epileptic encephalopathy: Two case reports and literature review. (PMID:33914968)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hnrnpub	ENSDARG00000004735
danio_rerio	hnrnpua	ENSDARG00000015206
mus_musculus	Hnrnpu	ENSMUSG00000039630
rattus_norvegicus	Hnrnpu	ENSRNOG00000033790

Paralogs (2): HNRNPUL1 (ENSG00000105323), HNRNPUL2 (ENSG00000214753)

Protein

Protein identifiers

Heterogeneous nuclear ribonucleoprotein U — Q00839 (reviewed: Q00839)

Alternative names: GRIP120, Nuclear p120 ribonucleoprotein, Scaffold-attachment factor A, p120, pp120

All UniProt accessions (19): Q00839, A0A087WVI9, A0A087WZF3, A0A1W2PNG3, A0A1W2PP22, A0A1W2PP34, A0A1W2PP35, A0A1W2PPE9, A0A1W2PPH7, A0A1W2PPL4, A0A1W2PPS1, A0A1W2PQ74, A0A1W2PQD4, A0A1W2PQL0, A0A1W2PRI6, A0A1W2PRZ7, A0A1X7SBS1, A0A994J6V2, Q5RI18

UniProt curated annotations — full annotation on UniProt →

Function. DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mitotic cell progression. Plays a role in the regulation of interphase large-scale gene-rich chromatin organization through chromatin-associated RNAs (caRNAs) in a transcription-dependent manner, and thereby maintains genomic stability. Required for the localization of the long non-coding Xist RNA on the inactive chromosome X (Xi) and the subsequent initiation and maintenance of X-linked transcriptional gene silencing during X-inactivation. Plays a role as a RNA polymerase II (Pol II) holoenzyme transcription regulator. Promotes transcription initiation by direct association with the core-TFIIH basal transcription factor complex for the assembly of a functional pre-initiation complex with Pol II in a actin-dependent manner. Blocks Pol II transcription elongation activity by inhibiting the C-terminal domain (CTD) phosphorylation of Pol II and dissociates from Pol II pre-initiation complex prior to productive transcription elongation. Positively regulates CBX5-induced transcriptional gene silencing and retention of CBX5 in the nucleus. Negatively regulates glucocorticoid-mediated transcriptional activation. Key regulator of transcription initiation and elongation in embryonic stem cells upon leukemia inhibitory factor (LIF) signaling. Involved in the long non-coding RNA H19-mediated Pol II transcriptional repression. Participates in the circadian regulation of the core clock component BMAL1 transcription. Plays a role in the regulation of telomere length. Plays a role as a global pre-mRNA alternative splicing modulator by regulating U2 small nuclear ribonucleoprotein (snRNP) biogenesis. Plays a role in mRNA stability. Component of the CRD-mediated complex that promotes MYC mRNA stabilization. Enhances the expression of specific genes, such as tumor necrosis factor TNFA, by regulating mRNA stability, possibly through binding to the 3’-untranslated region (UTR). Plays a role in mitotic cell cycle regulation. Involved in the formation of stable mitotic spindle microtubules (MTs) attachment to kinetochore, spindle organization and chromosome congression. Phosphorylation at Ser-59 by PLK1 is required for chromosome alignement and segregation and progression through mitosis. Also contributes to the targeting of AURKA to mitotic spindle MTs. Binds to double- and single-stranded DNA and RNA, poly(A), poly(C) and poly(G) oligoribonucleotides. Binds to chromatin-associated RNAs (caRNAs). Associates with chromatin to scaffold/matrix attachment region (S/MAR) elements in a chromatin-associated RNAs (caRNAs)-dependent manner. Binds to the Xist RNA. Binds the long non-coding H19 RNA. Binds to SMN1/2 pre-mRNAs at G/U-rich regions. Binds to small nuclear RNAs (snRNAs). Binds to the 3’-UTR of TNFA mRNA. Binds (via RNA-binding RGG-box region) to the long non-coding Xist RNA; this binding is direct and bridges the Xist RNA and the inactive chromosome X (Xi). Also negatively regulates embryonic stem cell differentiation upon LIF signaling. Required for embryonic development. Binds to brown fat long non-coding RNA 1 (Blnc1); facilitates the recruitment of Blnc1 by ZBTB7B required to drive brown and beige fat development and thermogenesis. (Microbial infection) Negatively regulates immunodeficiency virus type 1 (HIV-1) replication by preventing the accumulation of viral mRNA transcripts in the cytoplasm.

Subunit / interactions. Oligomer (via ATPase domain and RNA-binding RGG-box region); oligomerization occurs upon ATP-binding in a chromatin-associated RNAs (caRNAs)- and transcription-dependent manner and is required for chromatin decompaction. ATP hydrolysis is required to cycle from an oligomeric to monomeric state to compact chromatin. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. Identified in the spliceosome C complex. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Associates with heterogeneous nuclear ribonucleoprotein (hnRNP) particles. Associates (via middle region) with the C-terminal domain (CTD) RNA polymerase II (Pol II) holoenzyme; this association occurs in a RNA-independent manner. Associates (via middle region) with the core-TFIIH basal transcription factor complex; this association inhibits the CTD phosphorylation of RNA polymerase II holoenzyme by down-regulating TFIIH kinase activity. Associates with the telomerase holoenzyme complex. Associates with spindle microtubules (MTs) in a TPX2-dependent manner. Interacts (via C-terminus) with actin; this interaction is direct and mediates association with the phosphorylated CTD of RNA polymerase II and is disrupted in presence of the long non-coding H19 RNA. Interacts with AURKA. Interacts (via C-terminus) with CBX5; this interaction is, at least in part, RNA-dependent. Interacts with CR2. Interacts with CRY1. Interacts (via C-terminus) with EP300; this interaction enhances DNA-binding to nuclear scaffold/matrix attachment region (S/MAR) elements. Interacts with ERBB4. Interacts with GEMIN5. Interacts with IGF2BP1. Interacts with IGF2BP2 and IGF2BP3. Interacts with NCL; this interaction occurs during mitosis. Interacts (via C-terminus) with NR3C1 (via C-terminus). Interacts with PLK1; this interaction induces phosphorylation of HNRNPU at Ser-59 in mitosis. Interacts with POU3F4. Interacts with SMARCA4; this interaction occurs in embryonic stem cells and stimulates global Pol II-mediated transcription. Interacts (via C-terminus) with TOP2A; this interaction protects the topoisomerase TOP2A from degradation and positively regulates the relaxation of supercoiled DNA by TOP2A in a RNA-dependent manner. Interacts with TPX2; this interaction recruits HNRNPU to spindle microtubules (MTs). Interacts with UBQLN2. Interacts (via RNA-binding RGG-box region) with ZBTB7B; the interaction facilitates the recruitment of long non-coding RNA Blnc1 by ZBTB7B. Interacts with ERCC6. (Microbial infection) Interacts with HIV-1 protein Rev.

Subcellular location. Nucleus. Nucleus matrix. Chromosome. Nucleus speckle. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centromere. Kinetochore. Spindle. Spindle pole. Midbody. Cell surface. Cytoplasmic granule.

Tissue specificity. Widely expressed.

Post-translational modifications. Cleaved at Asp-100 by CASP3 during T-cell apoptosis, resulting in a loss of DNA- and chromatin-binding activities. Extensively phosphorylated. Phosphorylated on Ser-59 by PLK1 and dephosphorylated by protein phosphatase 2A (PP2A) in mitosis. Arg-739 is dimethylated, probably to asymmetric dimethylarginine (Ref.8). Arg-733 is dimethylated, probably to asymmetric dimethylarginine. Citrullinated by PADI4.

Disease relevance. Developmental and epileptic encephalopathy 54 (DEE54) [MIM:617391] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The SAP domain is necessary for specific binding to nuclear scaffold/matrix attachment region (S/MAR) elements in DNA. The RNA-binding RGG-box region is necessary for its association with inactive X chromosome (Xi) regions and to chromatin-associated RNAs (caRNAs). Both the DNA-binding domain SAP and the RNA-binding RGG-box region are necessary for the localization of Xist RNA on the Xi. The ATPase and RNA-binding RGG-box regions are necessary for oligomerization.

Isoforms (2)

UniProt ID	Names	Canonical?
Q00839-1	1, Long	yes
Q00839-2	2, Short

RefSeq proteins (2): NP_004492, NP_114032* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001870	B30.2/SPRY	Domain
IPR003034	SAP_dom	Domain
IPR003877	SPRY_dom	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035778	SPRY_hnRNP_U	Domain
IPR036361	SAP_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily

Pfam: PF00622, PF02037, PF13671

UniProt features (81 total): modified residue 35, cross-link 14, compositionally biased region 11, region of interest 6, mutagenesis site 4, sequence variant 3, domain 2, initiator methionine 1, chain 1, binding site 1, site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00839-F1	65.89	0.38

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): 100–101 (cleavage; by casp3)

Ligand- & substrate-binding residues (1): 504–511

Post-translational modifications (49): 2, 4, 17, 21, 59, 66, 186, 187, 255, 265, 266, 267, 271, 286, 352, 516, 524, 532, 551, 565 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
59	no change in interaction with aurka, plk1 and tpx2. increases mitotic chromosome misalignment and chromosome segregation
59	increases mitotic chromosome misalignment and chromosome segregation defects and decreases time required to progress thr
100	no cleavage by caspases during apoptosis. inhibits casp3-induced cleavage in vitro.
616–620	loss of actin-binding.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 740 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, GOBP_AXO_DENDRITIC_TRANSPORT, DORSAM_HOXA9_TARGETS_UP, MORF_SMC1L1

GO Biological Process (46): negative regulation of transcription by RNA polymerase II (GO:0000122), alternative mRNA splicing, via spliceosome (GO:0000380), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA splicing, via spliceosome (GO:0000398), osteoblast differentiation (GO:0001649), chromatin organization (GO:0006325), RNA processing (GO:0006396), regulation of mitotic cell cycle (GO:0007346), dosage compensation by inactivation of X chromosome (GO:0009048), erythrocyte differentiation (GO:0030218), regulatory ncRNA-mediated heterochromatin formation (GO:0031048), negative regulation of telomere maintenance via telomerase (GO:0032211), circadian regulation of gene expression (GO:0032922), negative regulation of kinase activity (GO:0033673), negative regulation of transcription elongation by RNA polymerase II (GO:0034244), positive regulation of transcription by RNA polymerase II (GO:0045944), mRNA stabilization (GO:0048255), brown fat cell differentiation (GO:0050873), cell division (GO:0051301), maintenance of protein location in nucleus (GO:0051457), cardiac muscle cell development (GO:0055013), random inactivation of X chromosome (GO:0060816), CRD-mediated mRNA stabilization (GO:0070934), cellular response to glucocorticoid stimulus (GO:0071385), positive regulation of brown fat cell differentiation (GO:0090336), dendritic transport of messenger ribonucleoprotein complex (GO:0098963), negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900152), regulation of mitotic spindle assembly (GO:1901673), regulation of chromatin organization (GO:1902275), positive regulation of attachment of mitotic spindle microtubules to kinetochore (GO:1902425), protein localization to spindle microtubule (GO:1902889), RNA localization to chromatin (GO:1990280), cellular response to leukemia inhibitory factor (GO:1990830), adaptive thermogenesis (GO:1990845), positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity (GO:2000373), positive regulation of stem cell proliferation (GO:2000648), negative regulation of stem cell differentiation (GO:2000737), positive regulation of cytoplasmic translation (GO:2000767), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (32): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II complex binding (GO:0000993), TFIIH-class transcription factor complex binding (GO:0001097), DNA binding (GO:0003677), chromatin binding (GO:0003682), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), mRNA 3’-UTR binding (GO:0003730), actin binding (GO:0003779), ATP binding (GO:0005524), poly(A) binding (GO:0008143), snRNA binding (GO:0017069), poly(C) RNA binding (GO:0017130), chromatin DNA binding (GO:0031490), poly(G) binding (GO:0034046), piRNA binding (GO:0034584), pre-mRNA binding (GO:0036002), identical protein binding (GO:0042802), ribonucleoprotein complex binding (GO:0043021), protein-containing complex binding (GO:0044877), telomerase RNA binding (GO:0070034), RNA polymerase II C-terminal domain binding (GO:0099122), lncRNA binding (GO:0106222), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), nucleotide binding (GO:0000166), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (30): nuclear chromosome (GO:0000228), kinetochore (GO:0000776), spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), telomerase holoenzyme complex (GO:0005697), centrosome (GO:0005813), cytosol (GO:0005829), cell surface (GO:0009986), membrane (GO:0016020), nuclear matrix (GO:0016363), nuclear speck (GO:0016607), dendrite (GO:0030425), midbody (GO:0030496), protein-containing complex (GO:0032991), cytoplasmic ribonucleoprotein granule (GO:0036464), CRD-mediated mRNA stability complex (GO:0070937), catalytic step 2 spliceosome (GO:0071013), mitotic spindle (GO:0072686), inactive sex chromosome (GO:0098577), mitotic spindle midzone (GO:1990023), mitotic spindle microtubule (GO:1990498), ribonucleoprotein complex (GO:1990904), chromosome, centromeric region (GO:0000775), spliceosomal complex (GO:0005681), chromosome (GO:0005694), cytoplasm (GO:0005737), spindle (GO:0005819), cytoskeleton (GO:0005856), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
mRNA Splicing	1
Metabolism of RNA	1
mRNA 3’-end processing	1
Transcriptional regulation of brown and beige adipocyte differentiation	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
DNA binding	3
RNA binding	3
nuclear lumen	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
heterochromatin formation	2
nucleus	2
nucleic acid binding	2
poly-purine tract binding	2
spindle	2
catalytic complex	2
cytoplasm	2
mRNA splicing, via spliceosome	1
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
ossification	1
cell differentiation	1
cellular component organization	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
mitotic cell cycle	1
regulation of cell cycle	1
sex-chromosome dosage compensation	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
regulatory ncRNA-mediated gene silencing	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
circadian rhythm	1
regulation of gene expression	1
kinase activity	1
negative regulation of phosphorylation	1
negative regulation of catalytic activity	1

Protein interactions and networks

STRING

3374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNRNPU	DHX9	Q08211	965
HNRNPU	YBX1	P16990	954
HNRNPU	HNRNPC	P07910	916
HNRNPU	SYNCRIP	O60506	909
HNRNPU	HNRNPM	P52272	893
HNRNPU	HNRNPA0	Q13151	891
HNRNPU	HNRNPA1	P09651	877
HNRNPU	ZBTB7B	O15156	868
HNRNPU	HNRNPDL	O14979	863
HNRNPU	ACIN1	Q9UKV3	853
HNRNPU	HNRNPK	P61978	847
HNRNPU	NUCLEOLIN	P19338	822
HNRNPU	HNRNPH1	P31943	808
HNRNPU	HNRNPF	P52597	789
HNRNPU	RBMX	P38159	779

IntAct

468 interactions, top by confidence:

A	B	Type	Score
HNRNPU	HNRNPD	psi-mi:“MI:0915”(physical association)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IGF2BP1	HNRNPU	psi-mi:“MI:0403”(colocalization)	0.680
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
HMGB1	HNRNPU	psi-mi:“MI:0915”(physical association)	0.610
IGF2BP1	SYNCRIP	psi-mi:“MI:0914”(association)	0.580
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
BRIX1	HNRNPU	psi-mi:“MI:0915”(physical association)	0.560
SNRPA	HNRNPU	psi-mi:“MI:0915”(physical association)	0.560
TAF15	HNRNPU	psi-mi:“MI:0915”(physical association)	0.540
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
UBQLN2	HNRNPU	psi-mi:“MI:0915”(physical association)	0.510
CDKN2A	HNRNPU	psi-mi:“MI:0915”(physical association)	0.510
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
HMGB1	UBC	psi-mi:“MI:0914”(association)	0.480
RBM45	HNRNPDL	psi-mi:“MI:0914”(association)	0.460

BioGRID (1486): HNRNPU (Affinity Capture-MS), HNRNPU (Affinity Capture-MS), HNRNPU (Affinity Capture-MS), HNRNPU (Affinity Capture-MS), HNRNPU (Affinity Capture-Western), ACTB (Reconstituted Complex), POLR2A (Reconstituted Complex), KAT2B (Reconstituted Complex), HNRNPU (Affinity Capture-Western), POLR2A (Affinity Capture-Western), KAT2B (Affinity Capture-Western), HNRNPU (Reconstituted Complex), HNRNPU (Affinity Capture-MS), HNRNPU (Affinity Capture-RNA), HNRNPU (Affinity Capture-MS)

ESM2 similar proteins: A9RA82, B3EX35, B4H303, B4USW8, B5DKJ8, B7NZ88, B8LIX8, H2L2B8, O18017, O61577, O80377, O80770, O97472, P34308, P34498, P49736, P53621, P55861, P97310, Q00839, Q00PI9, Q09249, Q0J3D9, Q19537, Q27954, Q5U3S1, Q5XIK7, Q5ZMN2, Q6C710, Q6DIH3, Q6IMY8, Q7XTS4, Q8CIE6, Q8GWW8, Q8K0T4, Q8LI34, Q8VEK3, Q94AH9, Q9AUR7, Q9AUR8

Diamond homologs: Q00839, Q00PI9, Q1KMD3, Q55CP6, Q6IMY8, Q8VDM6, Q8VEK3, Q9BUJ2, Q9VNV3, A2VD92, P53076, Q0IIK5, Q19614, Q4R7L5, Q5NVJ8, Q5XH91, Q641Y8, Q90WU3, Q91VR5, Q92499, A0KEG9, A1CTZ6, A1DNG2, A1SZG4, A2QRY2, A3LZT3, A4R5B8, A4RBS3, A4RHF1, A4WG30, A5DZT7, A5UDI1, A5UI36, A6QUM7, A6R603, A6SCT6, A6ZRX0, A7ESL7, A7EYW0, A7MQI2

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
PRKDC	up-regulates	HNRNPU	phosphorylation
UBQLN2	“up-regulates quantity by stabilization”	HNRNPU	binding
HNRNPU	“up-regulates quantity by stabilization”	TNF	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	GADD45A	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	HEXIM1	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	HOXA2	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	IER3	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	NHLH2	“post transcriptional regulation”
HNRNPU	“up-regulates quantity by stabilization”	ZFY	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 203 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
RIP-mediated NFkB activation via ZBP1	6	29.9×	5e-06
MAP3K8 (TPL2)-dependent MAPK1/3 activation	5	26.4×	9e-05
TRAF6 mediated NF-kB activation	7	23.7×	2e-06
TAK1-dependent IKK and NF-kappa-B activation	8	17.8×	2e-06
Dengue Virus Genome Translation and Replication	7	16.4×	2e-05
Aggrephagy	7	12.9×	1e-04
Selective autophagy	5	10.3×	4e-03
Activation of NF-kappaB in B cells	7	10.2×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	5	28.6×	1e-04
non-canonical NF-kappaB signal transduction	5	24.4×	2e-04
canonical NF-kappaB signal transduction	8	16.9×	2e-05
mRNA stabilization	7	14.8×	8e-05
positive regulation of translation	9	11.8×	2e-05
intrinsic apoptotic signaling pathway	5	10.4×	6e-03
negative regulation of translation	9	10.2×	6e-05
autophagosome maturation	5	10.2×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1197 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	106
Likely pathogenic	40
Uncertain significance	358
Likely benign	507
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064459	NM_031844.3(HNRNPU):c.1282del (p.Gly429fs)	Pathogenic
1064460	NM_031844.3(HNRNPU):c.143_149del (p.Gly48fs)	Pathogenic
1066807	NM_031844.3(HNRNPU):c.1118-1G>A	Pathogenic
1073238	NM_031844.3(HNRNPU):c.2256_2260del (p.Tyr753fs)	Pathogenic
1073511	NM_031844.3(HNRNPU):c.2291_2294dup (p.Tyr765Ter)	Pathogenic
1074368	NM_031844.3(HNRNPU):c.562_577del (p.Ser188fs)	Pathogenic
1075142	NM_031844.3(HNRNPU):c.1157dup (p.Thr388fs)	Pathogenic
1172594	NM_031844.3(HNRNPU):c.1674dup (p.Ala559fs)	Pathogenic
1174635	NM_031844.3(HNRNPU):c.651_660dup (p.Gly221fs)	Pathogenic
1219744	NM_031844.3(HNRNPU):c.2168-1G>T	Pathogenic
1298471	NM_031844.3(HNRNPU):c.1060_1061del (p.Asp353_Ile354insTer)	Pathogenic
1325815	NM_031844.3(HNRNPU):c.1230+1G>C	Pathogenic
1343373	NM_031844.3(HNRNPU):c.1665_1666del (p.Leu556fs)	Pathogenic
1390163	NM_031844.3(HNRNPU):c.2006dup (p.Tyr669Ter)	Pathogenic
1414731	NM_031844.3(HNRNPU):c.325G>T (p.Glu109Ter)	Pathogenic
1434352	NM_031844.3(HNRNPU):c.2210dup (p.Gln738fs)	Pathogenic
1452212	NM_031844.3(HNRNPU):c.730_731del (p.Arg244fs)	Pathogenic
1685881	NM_031844.3(HNRNPU):c.1905_1906del (p.Lys635fs)	Pathogenic
1685882	NM_031844.3(HNRNPU):c.804-9_804-6del	Pathogenic
1685883	NM_031844.3(HNRNPU):c.223G>T (p.Glu75Ter)	Pathogenic
1685884	NM_031844.3(HNRNPU):c.112C>A (p.Leu38Ile)	Pathogenic
1699947	NM_031844.3(HNRNPU):c.1320_1321del (p.Gly441fs)	Pathogenic
1700096	NM_031844.3(HNRNPU):c.551del (p.Ala184fs)	Pathogenic
1706354	NM_031844.3(HNRNPU):c.817C>T (p.Gln273Ter)	Pathogenic
1727731	NM_031844.3(HNRNPU):c.310dup (p.Met104fs)	Pathogenic
1787847	NM_031844.3(HNRNPU):c.2217_2218del (p.Gly740fs)	Pathogenic
2003133	NM_031844.3(HNRNPU):c.226C>T (p.Gln76Ter)	Pathogenic
2009944	NM_031844.3(HNRNPU):c.336_351del (p.Ala113fs)	Pathogenic
2017677	NM_031844.3(HNRNPU):c.1122del (p.Glu375fs)	Pathogenic
2023576	NM_031844.3(HNRNPU):c.1639del (p.Ala547fs)	Pathogenic

SpliceAI

2354 predictions. Top by Δscore:

Variant	Effect	Δscore
1:244841942:A:AG	acceptor_gain	1.0000
1:244841943:G:GG	acceptor_gain	1.0000
1:244842268:C:G	donor_gain	1.0000
1:244843038:AAG:A	acceptor_gain	1.0000
1:244843039:A:G	acceptor_gain	1.0000
1:244854400:T:TA	donor_gain	1.0000
1:244854971:A:AC	donor_gain	1.0000
1:244854971:ACAC:A	donor_gain	1.0000
1:244854971:ACACC:A	donor_gain	1.0000
1:244854972:C:CC	donor_gain	1.0000
1:244854972:CA:C	donor_gain	1.0000
1:244854972:CACC:C	donor_gain	1.0000
1:244854972:CACCC:C	donor_gain	1.0000
1:244855045:C:CC	acceptor_gain	1.0000
1:244855605:GGGG:G	acceptor_gain	1.0000
1:244855606:GGG:G	acceptor_gain	1.0000
1:244855607:GG:G	acceptor_gain	1.0000
1:244855609:C:CC	acceptor_gain	1.0000
1:244855609:CTA:C	acceptor_loss	1.0000
1:244855898:A:C	donor_gain	1.0000
1:244855905:T:TA	donor_gain	1.0000
1:244855908:T:TA	donor_gain	1.0000
1:244856059:T:TA	donor_gain	1.0000
1:244856154:GTTTC:G	acceptor_gain	1.0000
1:244856155:TTTC:T	acceptor_gain	1.0000
1:244856156:TTC:T	acceptor_gain	1.0000
1:244856157:TC:T	acceptor_gain	1.0000
1:244856158:CC:C	acceptor_gain	1.0000
1:244856158:CCTG:C	acceptor_loss	1.0000
1:244856159:C:CC	acceptor_gain	1.0000

AlphaMissense

5446 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:244856143:G:T	P643Q	1.000
1:244856458:T:A	K637N	1.000
1:244856458:T:G	K637N	1.000
1:244856462:A:C	M636R	1.000
1:244856462:A:G	M636T	1.000
1:244856521:T:A	R616S	1.000
1:244856521:T:G	R616S	1.000
1:244856522:C:G	R616T	1.000
1:244856552:A:T	V606D	1.000
1:244856555:A:T	V605E	1.000
1:244856558:A:T	V604D	1.000
1:244856561:G:T	A603D	1.000
1:244856562:C:G	A603P	1.000
1:244856567:C:G	R601P	1.000
1:244856572:G:C	F599L	1.000
1:244856572:G:T	F599L	1.000
1:244856573:A:G	F599S	1.000
1:244856574:A:G	F599L	1.000
1:244856574:A:T	F599I	1.000
1:244856581:A:C	F596L	1.000
1:244856581:A:T	F596L	1.000
1:244856582:A:C	F596C	1.000
1:244856582:A:G	F596S	1.000
1:244856583:A:C	F596V	1.000
1:244856583:A:G	F596L	1.000
1:244856583:A:T	F596I	1.000
1:244856593:T:A	K592N	1.000
1:244856593:T:G	K592N	1.000
1:244856595:T:C	K592E	1.000
1:244856596:T:A	R591S	1.000

dbSNP variants (sampled 300 via entrez): RS1000268523 (1:244861496 G>A), RS1000449137 (1:244865220 C>G,T), RS1000586282 (1:244862771 C>T), RS1000611221 (1:244860782 T>A), RS1001114629 (1:244850717 C>T), RS1001168123 (1:244854559 T>C), RS1001168587 (1:244849855 C>T), RS1001230666 (1:244850969 T>A,G), RS1001439129 (1:244858180 C>T), RS1001851109 (1:244859923 G>A,T), RS1001890098 (1:244857863 T>A,C), RS1001923613 (1:244864770 A>G,T), RS1002035067 (1:244853585 G>C,T), RS1002090274 (1:244860167 G>A), RS1002262064 (1:244864506 G>A,C,T)

Disease associations

OMIM: gene MIM:602869 | disease phenotypes: MIM:617391, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 54	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (6): developmental and epileptic encephalopathy, 54 (MONDO:0033363), intellectual disability (MONDO:0001071), developmental and epileptic encephalopathy, 1 (MONDO:0010632), autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000384	Preauricular skin tag
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001510	Growth delay
HP:0001671	Abnormal cardiac septum morphology
HP:0002007	Frontal bossing
HP:0002069	Bilateral tonic-clonic seizure

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296007 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.71	Kd	19.46	nM	CHEMBL3752910
7.71	ED50	19.46	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 12 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148538: Binding affinity to human HNRNPU incubated for 45 mins by Kinobead based pull down assay	kd	0.0195	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, affects expression, decreases expression, decreases methylation	8
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
bisphenol A	decreases expression, increases methylation	2
cobaltous chloride	decreases expression	2
bisphenol S	affects cotreatment, increases methylation, increases expression	2
Fulvestrant	affects cotreatment, increases methylation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	increases methylation, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
beauvericin	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
cyclic 3’,5’-uridine monophosphate	affects binding	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118557	Binding	Binding affinity to HNRNPU in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

300 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
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)