EXOSC9

Summary

EXOSC9 (exosome component 9, HGNC:9137) is a protein-coding gene on chromosome 4q27, encoding Exosome complex component RRP45 (Q06265). Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. It is a common-essential gene (DepMap: required in 90.5% of cancer cell lines).

This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5393 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia, type 1D (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 332 total — 22 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 90.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_005033

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9137
Approved symbol	EXOSC9
Name	exosome component 9
Location	4q27
Locus type	gene with protein product
Status	Approved
Aliases	PM/Scl-75, Rrp45p, RRP45, p5, p6
Ensembl gene	ENSG00000123737
Ensembl biotype	protein_coding
OMIM	606180
Entrez	5393

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000243498, ENST00000379663, ENST00000503139, ENST00000503236, ENST00000506201, ENST00000508212, ENST00000509800, ENST00000509980, ENST00000511132, ENST00000511454, ENST00000512454, ENST00000513654, ENST00000876433, ENST00000940328, ENST00000940329, ENST00000940330, ENST00000940331, ENST00000962073, ENST00000962074

RefSeq mRNA: 2 — MANE Select: NM_005033 NM_001034194, NM_005033

CCDS: CCDS34057, CCDS3722

Canonical transcript exons

ENST00000243498 — 12 exons

Exon	Start	End
ENSE00003502554	121816369	121816447
ENSE00003512764	121802915	121803017
ENSE00003544472	121811583	121811671
ENSE00003552850	121802674	121802793
ENSE00003568257	121804622	121804759
ENSE00003586315	121801827	121801921
ENSE00003624835	121809967	121810099
ENSE00003637944	121813234	121813380
ENSE00003659995	121807540	121807622
ENSE00003786405	121813866	121814047
ENSE00003898057	121816772	121817021
ENSE00003904075	121801323	121801490

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 98.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.5335 / max 664.7939, expressed in 1809 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49520	26.2947	1808
49521	0.2389	127

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.70	gold quality
oocyte	CL:0000023	97.95	gold quality
calcaneal tendon	UBERON:0003701	94.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.40	gold quality
buccal mucosa cell	CL:0002336	94.01	gold quality
testis	UBERON:0000473	93.71	gold quality
left testis	UBERON:0004533	93.56	gold quality
right testis	UBERON:0004534	93.34	gold quality
ventricular zone	UBERON:0003053	92.77	gold quality
ganglionic eminence	UBERON:0004023	91.94	gold quality
tendon	UBERON:0000043	90.72	gold quality
embryo	UBERON:0000922	90.62	gold quality
lymph node	UBERON:0000029	90.06	gold quality
sperm	CL:0000019	89.70	gold quality
granulocyte	CL:0000094	89.60	gold quality
monocyte	CL:0000576	89.58	gold quality
mononuclear cell	CL:0000842	89.53	gold quality
leukocyte	CL:0000738	89.50	gold quality
tibial nerve	UBERON:0001323	89.22	gold quality
cerebellar hemisphere	UBERON:0002245	89.18	gold quality
cerebellar cortex	UBERON:0002129	88.99	gold quality
islet of Langerhans	UBERON:0000006	88.79	gold quality
bone marrow	UBERON:0002371	88.67	gold quality
rectum	UBERON:0001052	88.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.47	gold quality
male germ cell	CL:0000015	88.31	gold quality
cortical plate	UBERON:0005343	88.30	gold quality
tonsil	UBERON:0002372	88.21	gold quality
body of uterus	UBERON:0009853	88.19	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

24 targeting EXOSC9, 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-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
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-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-188-5P	97.89	67.01	756
HSA-MIR-6866-3P	97.38	66.94	748
HSA-MIR-597-3P	96.46	68.03	1035

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements, possibly by direct binding of PM/Scl-75 to these RNA regions. (PMID:11782436)
• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• The association of the human PM/Scl-75 autoantigen with the exosome is dependent on a newly identified N terminus. (PMID:12788944)
• PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome. (PMID:14872500)
• Although not required for exosome stability, PM/Scl-100 and PM/Scl-75 are involved in mRNA degradation. (PMID:17545563)
• variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies. (PMID:29727687)
• Expanded PCH1D phenotype linked to EXOSC9 mutation. (PMID:30690203)
• EXOSC9 depletion attenuates P-body formation, stress resistance, and tumorigenicity of cancer cells. (PMID:32518284)
• Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy. (PMID:33040083)
• Exosc9 Initiates SUMO-Dependent lncRNA TERRA Degradation to Impact Telomeric Integrity in Endocrine Therapy Insensitive Hormone Receptor-Positive Breast Cancer. (PMID:37887339)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc9	ENSDARG00000006392
mus_musculus	Exosc9	ENSMUSG00000027714
rattus_norvegicus	Exosc9	ENSRNOG00000014674
drosophila_melanogaster	Rrp45	FBGN0030789
caenorhabditis_elegans		WBGENE00018154

Paralogs (2): EXOSC7 (ENSG00000075914), EXOSC8 (ENSG00000120699)

Protein

Protein identifiers

Exosome complex component RRP45 — Q06265 (reviewed: Q06265)

Alternative names: Autoantigen PM/Scl 1, Exosome component 9, P75 polymyositis-scleroderma overlap syndrome-associated autoantigen, Polymyositis/scleroderma autoantigen 1, Polymyositis/scleroderma autoantigen 75 kDa

All UniProt accessions (6): D6R905, D6RA17, D6RAP4, D6RIY6, Q06265, H0Y9L5

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding ‘pervasive’ transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3’ untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC9 binds to ARE-containing RNAs.

Subunit / interactions. Component of the RNA exosome core complex (Exo-9), composed of EXOSC1, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7, EXOSC8 and EXOSC9; within the complex interacts with EXOSC3, EXOSC4, EXOSC5 and DIS3. The catalytically inactive RNA exosome core complex (Exo-9) associates with the catalytic subunit EXOSC10/RRP6. Exo-9 may associate with DIS3 to form the nucleolar exosome complex, or DIS3L to form the cytoplasmic exosome complex. Exo-9 is formed by a hexameric base ring consisting of the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and a cap ring consisting of EXOSC1, EXOSC2 and EXOSC3. The RNA exosome complex associates with cofactors C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4. Interacts (via C-terminus region) with SETX (via N-terminus domain); the interaction enhances SETX sumoylation. Interacts with DIS3; the interaction is direct.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Nucleoplasm Nucleus. Nucleolus Nucleus.

Disease relevance. Pontocerebellar hypoplasia 1D (PCH1D) [MIM:618065] An autosomal recessive neurologic disorder with onset at birth or in infancy, and characterized by progressive axonal motor neuronopathy, severe generalized hypotonia, respiratory insufficiency, and cerebellar atrophy. Death in childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RNase PH family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q06265-1	1, PM/SCL-75c-alpha	yes
Q06265-2	2, PM/SCL-75c-beta
Q06265-3	3, PM/SCL-75a-alpha
Q06265-4	4, PM/SCL-75a-beta

RefSeq proteins (2): NP_001029366, NP_005024* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001247	ExoRNase_PH_dom1	Domain
IPR015847	ExoRNase_PH_dom2	Domain
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027408	PNPase/RNase_PH_dom_sf	Homologous_superfamily
IPR033100	Rrp45	Family
IPR036345	ExoRNase_PH_dom2_sf	Homologous_superfamily
IPR050590	Exosome_comp_Rrp42_subfam	Family

Pfam: PF01138, PF03725

UniProt features (61 total): strand 18, modified residue 10, helix 8, mutagenesis site 5, turn 5, sequence variant 4, region of interest 3, cross-link 3, splice variant 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9G8M	ELECTRON MICROSCOPY	3.3
2NN6	X-RAY DIFFRACTION	3.35
9G8O	ELECTRON MICROSCOPY	3.4
6D6Q	ELECTRON MICROSCOPY	3.45
6D6R	ELECTRON MICROSCOPY	3.45
9G8N	ELECTRON MICROSCOPY	3.7
6H25	ELECTRON MICROSCOPY	3.8
9G8P	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06265-F1	77.44	0.57

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 (13): 392, 394, 297, 297, 419, 409, 411, 325, 65, 327, 297, 306, 346

Mutagenesis-validated functional residues (5):

Position	Phenotype
388–391	abolishes interaction with setx.
390–391	abolishes interaction with setx.
395–398	abolishes interaction with setx.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 327 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_RIBOSOME_BIOGENESIS, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_NUCLEASE_ACTIVITY, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, WEI_MYCN_TARGETS_WITH_E_BOX, MUELLER_PLURINET, GOBP_RNA_SURVEILLANCE, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_MATURATION_OF_5_8S_RRNA_FROM_TRICISTRONIC_RRNA_TRANSCRIPT_SSU_RRNA_5_8S_RRNA_LSU_RRNA

GO Biological Process (16): exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000467), nuclear-transcribed mRNA catabolic process (GO:0000956), rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), mRNA catabolic process (GO:0006402), immune response (GO:0006955), rRNA catabolic process (GO:0016075), positive regulation of cell growth (GO:0030307), U1 snRNA 3’-end processing (GO:0034473), U4 snRNA 3’-end processing (GO:0034475), U5 snRNA 3’-end processing (GO:0034476), positive regulation of transcription by RNA polymerase II (GO:0045944), nuclear mRNA surveillance (GO:0071028), nuclear polyadenylation-dependent rRNA catabolic process (GO:0071035), TRAMP-dependent tRNA surveillance pathway (GO:0071038)

GO Molecular Function (5): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), mRNA 3’-UTR AU-rich region binding (GO:0035925), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (12): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), nuclear chromosome (GO:0000228), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062), nucleolar exosome (RNase complex) (GO:0101019), exoribonuclease complex (GO:1905354)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Regulation of mRNA stability by proteins that bind AU-rich elements	3
PERK regulates gene expression	1
Deadenylation-dependent mRNA decay	1
rRNA processing in the nucleus and cytosol	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	4
snRNA 3’-end processing	3
nuclear RNA surveillance	3
cellular anatomical structure	3
rRNA metabolic process	2
RNA catabolic process	2
exosome (RNase complex)	2
nucleus	2
cytoplasm	2
intracellular anatomical structure	2
maturation of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1
rRNA 3’-end processing	1
mRNA catabolic process	1
RNA processing	1
ribosome biogenesis	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
negative regulation of gene expression	1
mRNA metabolic process	1
immune system process	1
response to stimulus	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
nuclear-transcribed mRNA catabolic process	1
tRNA surveillance	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
mRNA 3’-UTR binding	1
DNA-binding transcription factor binding	1
binding	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

2171 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC9	EXOSC5	Q9NQT4	999
EXOSC9	EXOSC4	Q9NPD3	999
EXOSC9	EXOSC3	Q9NQT5	999
EXOSC9	EXOSC6	Q5RKV6	999
EXOSC9	EXOSC10	Q01780	998
EXOSC9	EXOSC1	Q9Y3B2	997
EXOSC9	EXOSC7	Q15024	991
EXOSC9	EXOSC8	Q96B26	991
EXOSC9	EXOSC2	Q13868	943
EXOSC9	DIS3	Q9Y2L1	929
EXOSC9	DIS3L	Q8TF46	859
EXOSC9	MTREX	P42285	759
EXOSC9	SETX	Q7Z333	756
EXOSC9	C1D	Q13901	745
EXOSC9	ZCCHC7	Q8N3Z6	666

IntAct

109 interactions, top by confidence:

A	B	Type	Score
EXOSC4	EXOSC9	psi-mi:“MI:0915”(physical association)	0.900
EXOSC2	EXOSC10	psi-mi:“MI:0914”(association)	0.840
EXOSC4	EXOSC10	psi-mi:“MI:0914”(association)	0.840
EXOSC1	EXOSC10	psi-mi:“MI:0915”(physical association)	0.810
EXOSC1	EXOSC10	psi-mi:“MI:0914”(association)	0.810
EXOSC3	EXOSC10	psi-mi:“MI:0914”(association)	0.790
DIS3	EXOSC10	psi-mi:“MI:0914”(association)	0.740
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC9	EXOSC10	psi-mi:“MI:0914”(association)	0.640
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
DIS3L	EXOSC9	psi-mi:“MI:0914”(association)	0.600
UBE2I	EXOSC9	psi-mi:“MI:0915”(physical association)	0.550
EXOSC4	MTREX	psi-mi:“MI:0914”(association)	0.530
PHF10	ACTL6A	psi-mi:“MI:0914”(association)	0.530
EXOSC2	MTREX	psi-mi:“MI:0914”(association)	0.530
EXOSC4	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
EXOSC7	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
EXOSC8	PXN	psi-mi:“MI:0914”(association)	0.530
EXOSC7	MTREX	psi-mi:“MI:0914”(association)	0.530
MPHOSPH6	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
DIS3L	EIF4E2	psi-mi:“MI:0914”(association)	0.530

BioGRID (252): EXOSC9 (Two-hybrid), EXOSC9 (Affinity Capture-MS), EXOSC9 (Reconstituted Complex), EXOSC9 (Affinity Capture-MS), EXOSC9 (Affinity Capture-MS), EXOSC9 (Affinity Capture-MS), EXOSC1 (Co-fractionation), EXOSC10 (Co-fractionation), EXOSC2 (Co-fractionation), EXOSC3 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC5 (Co-fractionation), EXOSC6 (Co-fractionation), EXOSC7 (Co-fractionation), EXOSC9 (Co-fractionation)

ESM2 similar proteins: A2RVK7, A2X0Q3, A6QLJ3, O00442, O23617, O81147, O81852, P0CT46, P31754, P37142, P48605, P49080, P49368, P80318, Q01415, Q06265, Q14181, Q2HJ88, Q2KHU3, Q3SWZ4, Q3T0K2, Q4QR75, Q4R3J0, Q4R963, Q5NVF9, Q5R6J8, Q5R7P3, Q5RCW2, Q5RGJ5, Q5XJQ5, Q69LE7, Q6P502, Q6STH5, Q6YXZ7, Q7YRA3, Q84T68, Q8C3X4, Q8GZQ3, Q8K1R3, Q8N442

Diamond homologs: A2C412, A4QEY2, A4YJR3, A5E8I9, A6Q4N2, B2V890, B3EH06, B3EMN6, B5YFY8, B6YSE7, B8I2R5, C1DTW6, C3MQ47, C3MVG5, C3N5R4, C3NED0, C3NHC2, C3PH09, C4KHE3, C4LJ74, C5A2B8, O26778, O29756, O59224, O74918, Q05636, Q06265, Q0W2Y7, Q10205, Q15024, Q2GGA4, Q2KHU3, Q3SW80, Q3SWZ4, Q3YSC4, Q47RU5, Q4QR75, Q54VM4, Q5FHK5, Q5HBH6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	EXOSC9	phosphorylation
EXOSC9	“form complex”	Exosome_Complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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
mRNA decay by 3’ to 5’ exoribonuclease	8	73.2×	7e-12
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	8	65.1×	1e-11
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	8	65.1×	1e-11
KSRP (KHSRP) binds and destabilizes mRNA	8	65.1×	1e-11
Nuclear RNA decay	15	59.4×	3e-21
ATF4 activates genes in response to endoplasmic reticulum stress	8	41.8×	7e-10
SARS-CoV-1 modulates host translation machinery	5	19.8×	2e-04
Major pathway of rRNA processing in the nucleolus and cytosol	22	17.4×	2e-19

GO biological processes:

GO term	Partners	Fold	FDR
rRNA catabolic process	6	62.6×	2e-08
maturation of 5.8S rRNA	5	55.4×	1e-06
RNA catabolic process	11	52.7×	5e-14
RNA processing	12	27.6×	3e-12
rRNA processing	15	22.4×	5e-14
autophagosome maturation	5	18.5×	3e-04
ribosomal small subunit biogenesis	6	14.4×	2e-04
cytoplasmic translation	7	13.7×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	5
Uncertain significance	143
Likely benign	110
Benign	32

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1388577	NM_005033.3(EXOSC9):c.1058_1059del (p.Asp352_Ser353insTer)	Pathogenic
1396946	NC_000004.12:g.121813865GT[1]	Pathogenic
1407196	NM_005033.3(EXOSC9):c.1157-176del	Pathogenic
1433763	NM_005033.3(EXOSC9):c.881_905dup (p.Pro302_Ile303insSerIleTer)	Pathogenic
1468857	NM_005033.3(EXOSC9):c.1062del (p.Lys355fs)	Pathogenic
1687055	NM_005033.3(EXOSC9):c.239T>G (p.Leu80Arg)	Pathogenic
1687056	NM_005033.3(EXOSC9):c.484dup (p.Arg162fs)	Pathogenic
1687057	NM_005033.3(EXOSC9):c.151G>C (p.Gly51Arg)	Pathogenic
1899880	NM_005033.3(EXOSC9):c.1034del (p.Asn345fs)	Pathogenic
1964976	NM_005033.3(EXOSC9):c.129del (p.Asp42_Tyr43insTer)	Pathogenic
2075346	NM_005033.3(EXOSC9):c.968C>G (p.Ser323Ter)	Pathogenic
2112278	NM_005033.3(EXOSC9):c.1174_1175del (p.Ser392fs)	Pathogenic
2123806	NM_005033.3(EXOSC9):c.1157-182del	Pathogenic
2143770	NM_005033.3(EXOSC9):c.634C>T (p.Arg212Ter)	Pathogenic
2778095	NM_005033.3(EXOSC9):c.283C>T (p.Gln95Ter)	Pathogenic
2812511	NM_005033.3(EXOSC9):c.347_348del (p.Ile116fs)	Pathogenic
2878488	NM_005033.3(EXOSC9):c.1098del (p.Ile367fs)	Pathogenic
2968175	NM_005033.3(EXOSC9):c.310C>T (p.Arg104Ter)	Pathogenic
2993571	NM_005033.3(EXOSC9):c.772_781del (p.Val258fs)	Pathogenic
3009337	NM_005033.3(EXOSC9):c.249_250dup (p.Gln84fs)	Pathogenic
3609457	NM_005033.3(EXOSC9):c.1125_1126del (p.Gly376fs)	Pathogenic
3683294	NM_005033.3(EXOSC9):c.1151_1152insGGTTAGGTAGGTGACA (p.Ser384delinsArgValArgTer)	Pathogenic
1375211	NM_005033.3(EXOSC9):c.281+1G>T	Likely pathogenic
1943099	NM_005033.3(EXOSC9):c.1156+2T>A	Likely pathogenic
2130665	NM_005033.3(EXOSC9):c.523-2A>G	Likely pathogenic
2811760	NM_005033.3(EXOSC9):c.1157-1G>T	Likely pathogenic
3385106	NM_005033.3(EXOSC9):c.827+1G>A	Likely pathogenic

SpliceAI

2074 predictions. Top by Δscore:

Variant	Effect	Δscore
4:121801487:GAAG:G	donor_gain	1.0000
4:121801488:AAGG:A	donor_loss	1.0000
4:121801489:AGGT:A	donor_loss	1.0000
4:121801492:T:G	donor_loss	1.0000
4:121801821:TTACA:T	acceptor_loss	1.0000
4:121801824:CAGC:C	acceptor_loss	1.0000
4:121801825:A:AC	acceptor_loss	1.0000
4:121801825:A:AG	acceptor_gain	1.0000
4:121801825:AGC:A	acceptor_gain	1.0000
4:121801825:AGCG:A	acceptor_gain	1.0000
4:121801826:G:GT	acceptor_gain	1.0000
4:121801826:GC:G	acceptor_gain	1.0000
4:121801826:GCG:G	acceptor_gain	1.0000
4:121801826:GCGG:G	acceptor_gain	1.0000
4:121801918:CAAGG:C	donor_loss	1.0000
4:121801919:AAG:A	donor_loss	1.0000
4:121801920:AGGTA:A	donor_loss	1.0000
4:121801921:GGTAA:G	donor_loss	1.0000
4:121801922:GTA:G	donor_loss	1.0000
4:121801923:T:A	donor_loss	1.0000
4:121801929:GATT:G	donor_gain	1.0000
4:121802672:A:AG	acceptor_gain	1.0000
4:121802673:G:A	acceptor_loss	1.0000
4:121802673:G:GA	acceptor_gain	1.0000
4:121802673:GA:G	acceptor_gain	1.0000
4:121802673:GAGT:G	acceptor_gain	1.0000
4:121802673:GAGTT:G	acceptor_gain	1.0000
4:121804609:A:G	acceptor_gain	1.0000
4:121804619:CAGGT:C	acceptor_loss	1.0000
4:121804748:G:GT	donor_gain	1.0000

AlphaMissense

2892 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:121801840:G:C	R27T	0.999
4:121801841:A:C	R27S	0.999
4:121801841:A:T	R27S	0.999
4:121802732:G:C	G74R	0.999
4:121801858:G:T	R33M	0.998
4:121802732:G:T	G74C	0.998
4:121802733:G:A	G74D	0.998
4:121802733:G:T	G74V	0.998
4:121802995:T:C	L121P	0.998
4:121803001:T:A	V123D	0.998
4:121804625:T:A	W130R	0.998
4:121804625:T:C	W130R	0.998
4:121807589:C:A	P191H	0.998
4:121807589:C:G	P191R	0.998
4:121801473:G:C	A17P	0.997
4:121801840:G:T	R27I	0.997
4:121801891:G:A	G44E	0.997
4:121802976:T:C	C115R	0.997
4:121802995:T:A	L121H	0.997
4:121804635:G:C	R133P	0.997
4:121807600:A:C	S195R	0.997
4:121807602:T:A	S195R	0.997
4:121807602:T:G	S195R	0.997
4:121810039:C:A	N226K	0.997
4:121810039:C:G	N226K	0.997
4:121811592:T:C	C250R	0.997
4:121801839:A:G	R27G	0.996
4:121801858:G:C	R33T	0.996
4:121802688:T:A	V59D	0.996
4:121804623:T:A	V129D	0.996

dbSNP variants (sampled 300 via entrez): RS1000264777 (4:121810728 G>T), RS1000941411 (4:121816724 C>G,T), RS1001019712 (4:121807808 T>TTA), RS1001152882 (4:121810402 G>A), RS1001262839 (4:121809779 G>A), RS1001616976 (4:121816600 T>G), RS10023020 (4:121803449 G>A), RS1002907773 (4:121803474 A>G), RS1003635615 (4:121805861 A>G), RS1003640171 (4:121808766 C>T), RS1003689443 (4:121800267 G>A), RS1003805276 (4:121799893 T>G), RS1004035406 (4:121814710 CCA>C), RS1004151726 (4:121802292 T>A), RS1004319533 (4:121808534 AT>A,ATT)

Disease associations

OMIM: gene MIM:606180 | disease phenotypes: MIM:618065, MIM:300867, MIM:607596

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia, type 1D	Strong	Autosomal recessive
pontocerebellar hypoplasia type 1	Supportive	Autosomal recessive

Mondo (4): pontocerebellar hypoplasia, type 1D (MONDO:0054844), Kabuki syndrome 2 (MONDO:0010465), pontocerebellar hypoplasia (MONDO:0020135), pontocerebellar hypoplasia type 1 (MONDO:0016396)

Orphanet (2): Kabuki syndrome (Orphanet:2322), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000369	Low-set ears
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000529	Progressive visual loss
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0001181	Adducted thumb
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001308	Tongue fasciculations
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001371	Flexion contracture

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004602_28	Mean corpuscular volume	9.000000e-21
GCST004630_142	Mean corpuscular hemoglobin	6.000000e-18
GCST90002403_434	Red blood cell count	5.000000e-14
GCST90020028_1957	Hip circumference adjusted for BMI	3.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C580383	Pontocerebellar Hypoplasia (supp.)
C548069	Pontocerebellar Hypoplasia Type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725197 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.64	Kd	2292	nM	CHEMBL5653589
5.51	ED50	3108	nM	CHEMBL5653589
5.47	IC50	3390	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 8 total; 2 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	2148354: Binding affinity to human EXOSC9 incubated for 45 mins by Kinobead based pull down assay	kd	2.2917	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178924: Inhibition of EXOSC9 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	3.3900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
jinfukang	decreases expression	1
incobotulinumtoxinA	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	decreases expression, affects cotreatment	1
Calcitriol	decreases expression, affects cotreatment	1
Carbamazepine	affects expression	1
Coumestrol	affects cotreatment, increases expression, affects reaction	1
Cuprizone	decreases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Mustard Gas	decreases expression	1
Piroxicam	decreases expression	1
Quercetin	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
CHEMBL5651396	Binding	Binding affinity to human EXOSC9 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)

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