EXOSC3

Summary

EXOSC3 (exosome component 3, HGNC:17944) is a protein-coding gene on chromosome 9p13.2, encoding Exosome complex component RRP40 (Q9NQT5). 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 98.8% of cancer cell lines).

This gene encodes a non-catalytic component of the human exosome, a complex with 3’-5’ exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 51010 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pontocerebellar hypoplasia type 1B (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 312 total — 22 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 45
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_016042

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17944
Approved symbol	EXOSC3
Name	exosome component 3
Location	9p13.2
Locus type	gene with protein product
Status	Approved
Aliases	hRrp40p, Rrp40p, RRP40, CGI-102, p10, hRrp-40
Ensembl gene	ENSG00000107371
Ensembl biotype	protein_coding
OMIM	606489
Entrez	51010

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 6 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000327304, ENST00000396521, ENST00000465229, ENST00000465860, ENST00000482614, ENST00000489414, ENST00000490516, ENST00000496910, ENST00000678095, ENST00000678588, ENST00000679059, ENST00000858037, ENST00000913387, ENST00000913388, ENST00000956473

RefSeq mRNA: 2 — MANE Select: NM_016042 NM_001002269, NM_016042

CCDS: CCDS35016, CCDS43805

Canonical transcript exons

ENST00000327304 — 4 exons

Exon	Start	End
ENSE00001763765	37779714	37780880
ENSE00001912640	37784721	37785064
ENSE00003532790	37781986	37782137
ENSE00003592129	37783914	37784063

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.0489 / max 143.1427, expressed in 1810 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100745	20.9442	1809
100744	0.8638	492
100743	0.2409	93

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.03	gold quality
secondary oocyte	CL:0000655	98.12	gold quality
tendon of biceps brachii	UBERON:0008188	94.27	gold quality
adrenal tissue	UBERON:0018303	93.39	gold quality
calcaneal tendon	UBERON:0003701	93.22	gold quality
tendon	UBERON:0000043	92.52	gold quality
right testis	UBERON:0004534	92.02	gold quality
left testis	UBERON:0004533	91.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.39	gold quality
testis	UBERON:0000473	90.50	gold quality
stromal cell of endometrium	CL:0002255	89.59	gold quality
sperm	CL:0000019	89.24	gold quality
ganglionic eminence	UBERON:0004023	89.14	gold quality
right adrenal gland	UBERON:0001233	89.11	gold quality
adult organism	UBERON:0007023	88.97	gold quality
vermiform appendix	UBERON:0001154	88.81	gold quality
mucosa of transverse colon	UBERON:0004991	88.75	gold quality
colonic epithelium	UBERON:0000397	88.73	gold quality
right adrenal gland cortex	UBERON:0035827	88.30	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.77	gold quality
left adrenal gland	UBERON:0001234	87.76	gold quality
ventricular zone	UBERON:0003053	87.71	gold quality
adrenal gland	UBERON:0002369	87.67	gold quality
left adrenal gland cortex	UBERON:0035825	87.62	gold quality
leukocyte	CL:0000738	87.48	gold quality
monocyte	CL:0000576	87.42	gold quality
oral cavity	UBERON:0000167	87.36	gold quality
esophagus mucosa	UBERON:0002469	87.33	gold quality
colonic mucosa	UBERON:0000317	87.11	gold quality
bone marrow cell	CL:0002092	86.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting EXOSC3, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
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-6870-5P	99.99	68.55	2115
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-106A-3P	99.53	67.58	995
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-548AS-3P	99.12	69.12	2294

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• We identified a homozygous mutation [c.395A > C/p.D132A] in EXOSC3 in four patients with muscle hypotonia, developmental delay, spinal anterior horn involvement, and prolonged survival, consistent with the “mild PCH1 phenotype”. (PMID:23564332)
• The same mutation c.92G–>C, p.G31A in EXOSC3 was found in three unrelated Czech Roma patients with Pontocerebellar hypoplasia type 1 (PMID:23883322)
• The present study indicates that EXOSC3 mutations can underlie clinical phenotype not classifiable as pontocerebellar hypoplasia type 1. (PMID:23975261)
• study identified new nonsense and missense mutations in the EXOSC3 gene and showed mutations in this gene are exclusively found in pontocerebellar hypoplasia type 1 patients; there are evident genotype-phenotype correlations in EXOSC3-mediated PCH reflected in clinical outcome, age of death and pons hypoplasia (PMID:24524299)
• EXOSC3 mutations were linked to complicated hereditary spastic paraplegia. (PMID:25149867)
• Knock-down of rbm7, exosc8 and exosc3 in zebrafish showed a common pattern of defects in motor neurons and cerebellum. Our data indicate that impaired RNA metabolism may underlie the clinical phenotype by fine tuning gene expression which is essential for correct neuronal differentiation (PMID:27193168)
• Mutations of EXOSC3/Rrp40p associated with pontocerebellar hypoplasia with progressive cerebral atrophy impact ribosomal RNA processing functions of the exosome in S. cerevisiae. (PMID:28053271)
• This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of pontocerebellar hypoplasia type 1b. (PMID:28687512)
• A Drosophila model of Pontocerebellar Hypoplasia reveals a critical role for the RNA exosome in neurons. (PMID:32645003)
• Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form. (PMID:33462000)
• Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer. (PMID:34626022)
• Atypical hemolytic uremic syndrome induced by SARS-CoV2 infection in infants with EXOSC3 mutation. (PMID:35522339)
• Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival. (PMID:39176091)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc3	ENSDARG00000098334
		ENSDARG00000104246
mus_musculus	Exosc3	ENSMUSG00000028322
rattus_norvegicus	Exosc3	ENSRNOG00000012409
drosophila_melanogaster	Rrp40	FBGN0260648
caenorhabditis_elegans	exos-3	WBGENE00010325

Paralogs (1): EXOSC2 (ENSG00000130713)

Protein

Protein identifiers

Exosome complex component RRP40 — Q9NQT5 (reviewed: Q9NQT5)

Alternative names: Exosome component 3, Ribosomal RNA-processing protein 40, p10

All UniProt accessions (2): Q9NQT5, A0A7I2V328

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. EXOSC3 as peripheral part of the Exo-9 complex stabilizes the hexameric ring of RNase PH-domain subunits through contacts with EXOSC9 and EXOSC5.

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 EXOSC5 and EXOSC9. 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 with MPHOSPH6/MPP6; the interaction is direct. Interacts with GTPBP1. Interacts with ZC3HAV1. Interacts with DDX17 only in the presence of ZC3HAV1 in an RNA-independent manner. Interacts with DHX36; this interaction occurs in a RNase-insensitive manner. Interacts with HBS1L isoform 2.

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Disease relevance. Pontocerebellar hypoplasia 1B (PCH1B) [MIM:614678] A severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RRP40 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NQT5-1	1	yes
Q9NQT5-2	2

RefSeq proteins (2): NP_001002269, NP_057126* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004088	KH_dom_type_1	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR026699	Exosome_RNA_bind1/RRP40/RRP4	Family
IPR036612	KH_dom_type_1_sf	Homologous_superfamily
IPR037319	Rrp40_S1	Domain
IPR048541	RRP40_N	Domain
IPR049469	RRP40_KH-I	Domain

Pfam: PF15985, PF21261, PF21262

UniProt features (43 total): strand 21, sequence variant 6, helix 5, turn 4, sequence conflict 2, initiator methionine 1, chain 1, modified residue 1, cross-link 1, splice variant 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-Q9NQT5-F1	80.26	0.37

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 (2): 2, 151

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: 348 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_DNA_RECOMBINATION, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_B_CELL_ACTIVATION, GOMF_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_SNO_S_RNA_METABOLIC_PROCESS, GOBP_TRNA_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_B_CELL_MEDIATED_IMMUNITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY

GO Biological Process (17): 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), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), isotype switching (GO:0045190), positive regulation of isotype switching (GO:0045830), CUT catabolic process (GO:0071034), nuclear polyadenylation-dependent rRNA catabolic process (GO:0071035), TRAMP-dependent tRNA surveillance pathway (GO:0071038), poly(A)-dependent snoRNA 3’-end processing (GO:0071051), DNA metabolic process (GO:0006259), gene expression (GO:0010467), regulation of gene expression (GO:0010468)

GO Molecular Function (3): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (10): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nucleolar exosome (RNase complex) (GO:0101019)

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	3
cellular anatomical structure	3
gene expression	2
RNA catabolic process	2
nuclear RNA surveillance	2
exosome (RNase complex)	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
rRNA metabolic process	1
ribosome biogenesis	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
snRNA 3’-end processing	1
DNA modification	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of isotype switching	1
positive regulation of DNA recombination	1
positive regulation of B cell activation	1
positive regulation of developmental process	1
tRNA surveillance	1
sno(s)RNA 3’-end processing	1
nucleic acid metabolic process	1
macromolecule biosynthetic process	1
regulation of macromolecule biosynthetic process	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
binding	1

Protein interactions and networks

STRING

1980 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC3	EXOSC5	Q9NQT4	999
EXOSC3	EXOSC7	Q15024	999
EXOSC3	EXOSC4	Q9NPD3	999
EXOSC3	EXOSC9	Q06265	999
EXOSC3	EXOSC6	Q5RKV6	999
EXOSC3	EXOSC8	Q96B26	999
EXOSC3	EXOSC1	Q9Y3B2	999
EXOSC3	EXOSC2	Q13868	996
EXOSC3	EXOSC10	Q01780	962
EXOSC3	DIS3	Q9Y2L1	899
EXOSC3	SKIC2	Q15477	864
EXOSC3	MTREX	P42285	806
EXOSC3	RBM7	Q9Y580	804
EXOSC3	DIS3L	Q8TF46	794
EXOSC3	MPHOSPH6	Q99547	762

IntAct

101 interactions, top by confidence:

A	B	Type	Score
EXOSC5	EXOSC3	psi-mi:“MI:0915”(physical association)	0.910
EXOSC3	EXOSC2	psi-mi:“MI:0915”(physical association)	0.910
EXOSC5	EXOSC10	psi-mi:“MI:0914”(association)	0.890
EXOSC3	DIS3L	psi-mi:“MI:0915”(physical association)	0.850
EXOSC2	EXOSC10	psi-mi:“MI:0914”(association)	0.840
EXOSC4	EXOSC10	psi-mi:“MI:0914”(association)	0.840
Zc3hav1	EXOSC5	psi-mi:“MI:0914”(association)	0.810
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
EXOSC3	EXOSC10	psi-mi:“MI:0403”(colocalization)	0.790
EXOSC7	EXOSC10	psi-mi:“MI:0914”(association)	0.750
EXOSC3	DIS3	psi-mi:“MI:0915”(physical association)	0.740
DIS3	EXOSC10	psi-mi:“MI:0914”(association)	0.740
DIS3L	EXOSC2	psi-mi:“MI:0914”(association)	0.690
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
rep	MPHOSPH10	psi-mi:“MI:0914”(association)	0.660
EXOSC8	EXOSC10	psi-mi:“MI:0914”(association)	0.660
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640

BioGRID (249): EXOSC3 (Affinity Capture-RNA), EXOSC10 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), EXOSC7 (Affinity Capture-MS), MPHOSPH6 (Affinity Capture-MS), EXOSC8 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), HBS1L (Affinity Capture-MS), EXOSC9 (Affinity Capture-MS), DIS3L (Affinity Capture-MS), EXOSC5 (Affinity Capture-MS), MLLT3 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), EXOSC2 (Affinity Capture-MS), EXOSC1 (Affinity Capture-MS)

ESM2 similar proteins: A2AFS3, A5PJM7, A6QNS9, B1AR13, B5FWC0, D3ZVU9, D4ABL6, E9PV86, M0R7X9, O35972, O54804, O75618, P01134, P0C7P0, P48030, Q01134, Q0VCJ8, Q3SXP7, Q3SZB3, Q3T0E1, Q3UGX3, Q3UMR5, Q3ZBS2, Q3ZCQ8, Q4V8I4, Q5EA46, Q5RAJ8, Q5ZJB7, Q5ZMH6, Q6DN14, Q6ZN54, Q7Z5A7, Q7Z6G3, Q86W50, Q8CIW5, Q8N9F0, Q8NBA8, Q8TF64, Q91VA6, Q91WE9

Diamond homologs: O13903, Q08285, Q3T0E1, Q7KWX9, Q7TQK4, Q8IPX7, Q9NQT5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EXOSC3	“form complex”	Exosome_Complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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	9	131.1×	2e-16
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	9	116.5×	5e-16
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	9	116.5×	5e-16
KSRP (KHSRP) binds and destabilizes mRNA	9	116.5×	5e-16
Nuclear RNA decay	16	100.8×	3e-27
ATF4 activates genes in response to endoplasmic reticulum stress	9	74.9×	6e-14
rRNA processing in the nucleus and cytosol	7	23.0×	6e-07
Major pathway of rRNA processing in the nucleolus and cytosol	18	22.7×	3e-18

GO biological processes:

GO term	Partners	Fold	FDR
rRNA catabolic process	8	130.0×	3e-14
RNA catabolic process	12	89.6×	1e-18
maturation of 5.8S rRNA	5	86.3×	9e-08
RNA processing	14	50.2×	2e-18
rRNA processing	13	30.2×	2e-14
negative regulation of translation	7	22.5×	9e-07
ribosomal small subunit biogenesis	5	18.7×	2e-04
cytoplasmic translation	5	15.2×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	16
Uncertain significance	106
Likely benign	124
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
129023	NM_016042.4(EXOSC3):c.112del (p.Glu38fs)	Pathogenic
1322842	NM_016042.4(EXOSC3):c.382dup (p.Ile128fs)	Pathogenic
1525013	NM_016042.4(EXOSC3):c.404_407del (p.Gly135fs)	Pathogenic
183048	NM_016042.4(EXOSC3):c.571G>T (p.Gly191Cys)	Pathogenic
1996188	NM_016042.4(EXOSC3):c.301del (p.Trp101fs)	Pathogenic
2159070	NM_016042.4(EXOSC3):c.151C>T (p.Arg51Ter)	Pathogenic
2735274	NM_016042.4(EXOSC3):c.551del (p.Cys184fs)	Pathogenic
2757620	NM_016042.4(EXOSC3):c.422del (p.Leu141fs)	Pathogenic
2767586	NM_016042.4(EXOSC3):c.714G>A (p.Trp238Ter)	Pathogenic
280004	NM_016042.4(EXOSC3):c.155del (p.Pro52fs)	Pathogenic
2829110	NM_016042.4(EXOSC3):c.180del (p.Ser61fs)	Pathogenic
2855937	NM_016042.4(EXOSC3):c.174_183del (p.Arg58fs)	Pathogenic
2866577	NM_016042.4(EXOSC3):c.129del (p.Gly44fs)	Pathogenic
2912064	NM_016042.4(EXOSC3):c.1A>T (p.Met1Leu)	Pathogenic
2962578	NM_016042.4(EXOSC3):c.3G>T (p.Met1Ile)	Pathogenic
3016443	NM_016042.4(EXOSC3):c.3G>A (p.Met1Ile)	Pathogenic
31688	NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)	Pathogenic
31690	NM_016042.4(EXOSC3):c.294_303del (p.Val99fs)	Pathogenic
3366785	NM_016042.4(EXOSC3):c.660dup (p.Val221fs)	Pathogenic
3641160	NM_016042.4(EXOSC3):c.395_397del (p.Asp132del)	Pathogenic
3706994	NM_016042.4(EXOSC3):c.419_422del (p.Ser140fs)	Pathogenic
4294518	NM_016042.4(EXOSC3):c.552T>A (p.Cys184Ter)	Pathogenic
1329042	NM_016042.4(EXOSC3):c.624_626+1del	Likely pathogenic
1675306	NM_016042.4(EXOSC3):c.482A>G (p.Asp161Gly)	Likely pathogenic
1806093	NM_016042.4(EXOSC3):c.2T>G (p.Met1Arg)	Likely pathogenic
210965	NM_016042.4(EXOSC3):c.572G>A (p.Gly191Asp)	Likely pathogenic
2500779	NM_016042.4(EXOSC3):c.703G>A (p.Gly235Arg)	Likely pathogenic
2843410	NM_016042.4(EXOSC3):c.325-1G>T	Likely pathogenic
3075964	NM_016042.4(EXOSC3):c.112G>T (p.Glu38Ter)	Likely pathogenic
31692	NM_016042.4(EXOSC3):c.712T>C (p.Trp238Arg)	Likely pathogenic

SpliceAI

3259 predictions. Top by Δscore:

Variant	Effect	Δscore
9:37762529:T:A	acceptor_gain	1.0000
9:37768074:A:AG	acceptor_gain	1.0000
9:37768075:G:GG	acceptor_gain	1.0000
9:37768226:CTGGT:C	donor_loss	1.0000
9:37768227:TGGT:T	donor_loss	1.0000
9:37768228:GGTA:G	donor_loss	1.0000
9:37768229:G:GG	donor_gain	1.0000
9:37768229:GT:G	donor_loss	1.0000
9:37768230:T:A	donor_loss	1.0000
9:37769939:A:AG	acceptor_gain	1.0000
9:37769940:G:GG	acceptor_gain	1.0000
9:37769940:GTTA:G	acceptor_gain	1.0000
9:37770670:A:AG	acceptor_gain	1.0000
9:37770671:G:GA	acceptor_gain	1.0000
9:37770671:GCT:G	acceptor_gain	1.0000
9:37770738:AGGTA:A	donor_loss	1.0000
9:37770739:GGTA:G	donor_loss	1.0000
9:37770740:G:GG	donor_gain	1.0000
9:37776280:A:AG	acceptor_gain	1.0000
9:37776281:G:GG	acceptor_gain	1.0000
9:37781981:CTTA:C	donor_loss	1.0000
9:37781982:TTACT:T	donor_loss	1.0000
9:37781983:TACT:T	donor_loss	1.0000
9:37781984:A:AC	donor_gain	1.0000
9:37781985:C:CA	donor_gain	1.0000
9:37781985:C:CC	donor_gain	1.0000
9:37781985:C:CT	donor_loss	1.0000
9:37781985:CTTT:C	donor_gain	1.0000
9:37782025:T:TA	donor_gain	1.0000
9:37782138:C:T	acceptor_loss	1.0000

AlphaMissense

1764 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:37780803:C:A	G235V	1.000
9:37780805:A:C	N234K	1.000
9:37780805:A:T	N234K	1.000
9:37780812:C:T	G232E	1.000
9:37782072:A:C	C180W	1.000
9:37783926:T:A	R154S	1.000
9:37783926:T:G	R154S	1.000
9:37783927:C:G	R154T	1.000
9:37783935:T:A	K151N	1.000
9:37783935:T:G	K151N	1.000
9:37783937:T:C	K151E	1.000
9:37783950:A:C	F146L	1.000
9:37783950:A:T	F146L	1.000
9:37783952:A:G	F146L	1.000
9:37784026:A:T	V121E	1.000
9:37784032:C:T	G119D	1.000
9:37780791:A:T	V239D	0.999
9:37780795:A:G	W238R	0.999
9:37780795:A:T	W238R	0.999
9:37780797:A:T	I237K	0.999
9:37780803:C:T	G235E	0.999
9:37780806:T:A	N234I	0.999
9:37782073:C:T	C180Y	0.999
9:37782074:A:G	C180R	0.999
9:37782118:C:T	G165D	0.999
9:37782119:C:G	G165R	0.999
9:37783918:A:T	V157E	0.999
9:37783932:T:A	R152S	0.999
9:37783932:T:G	R152S	0.999
9:37783933:C:G	R152T	0.999

dbSNP variants (sampled 300 via entrez): RS1000151553 (9:37779819 G>A,C), RS1000235343 (9:37780095 T>C), RS1000242479 (9:37785290 C>T), RS1000288986 (9:37781045 A>T), RS1000463499 (9:37786371 G>T), RS1000837503 (9:37781615 G>C), RS1000962577 (9:37786868 C>A,T), RS1001245380 (9:37786566 T>A), RS1001449693 (9:37785749 C>T), RS1001561437 (9:37781407 C>T), RS1001793383 (9:37784664 CTCAA>C), RS1002245309 (9:37782748 A>G), RS1002846587 (9:37783992 A>G), RS1003114507 (9:37783499 A>G), RS1003599995 (9:37783718 A>G)

Disease associations

OMIM: gene MIM:606489 | disease phenotypes: MIM:614678, MIM:607596, MIM:607432, MIM:117000, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
pontocerebellar hypoplasia type 1B	Definitive	Autosomal recessive
pontocerebellar hypoplasia type 1	Supportive	Autosomal recessive

Mondo (8): pontocerebellar hypoplasia type 1B (MONDO:0013853), pontocerebellar hypoplasia (MONDO:0020135), congenital nervous system disorder (MONDO:0002320), pontocerebellar hypoplasia type 1 (MONDO:0016396), microcephaly (MONDO:0001149), lissencephaly spectrum disorders (MONDO:0018838), congenital myopathy (MONDO:0019952), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (5): Pontocerebellar hypoplasia type 1 (Orphanet:2254), Non-syndromic pontocerebellar hypoplasia (Orphanet:98523), Lissencephaly (Orphanet:48471), Congenital myopathy (Orphanet:97245), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000253	Progressive microcephaly
HP:0000486	Strabismus
HP:0000529	Progressive visual loss
HP:0000556	Retinal dystrophy
HP:0000565	Esotropia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000657	Oculomotor apraxia
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:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001760	Abnormal foot morphology
HP:0002059	Cerebral atrophy
HP:0002093	Respiratory insufficiency
HP:0002120	Cerebral cortical atrophy
HP:0002350	Cerebellar cyst

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D054082	Lissencephaly	C10.500.507.450.499; C16.131.666.507.450.499
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C580383	Pontocerebellar Hypoplasia (supp.)
C548069	Pontocerebellar Hypoplasia Type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment	2
Hydrogen Peroxide	affects expression, affects cotreatment, increases expression	2
Tretinoin	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
hydroquinone	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
K 7174	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Coumestrol	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Silicon Dioxide	increases expression	1
Theophylline	affects cotreatment, increases expression	1
Thiram	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C4P1	UAZTi009-A	Induced pluripotent stem cell	Female
CVCL_C4P3	UAZTi011-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT02020187	Not specified	COMPLETED	Aerobic Training in Patients With Congenital Myopathies
NCT03018184	Not specified	COMPLETED	Contractile Cross Sectional Areas and Muscle Strength in Patients With Congenital Myopathies
NCT04733976	Not specified	COMPLETED	Bullying in Youth With Muscular Dystrophy and Congenital Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
NCT07138963	Not specified	RECRUITING	Phenotype - Genotype Correlation in a Sample of Egyptian Patients With Congenital Myopathies and Congenital Muscular Dystrophies
NCT07415837	Not specified	RECRUITING	Evaluation of the Role of miR-1 in the Pathogenesis and as a Biomarker in Muscular Dystrophies and Congenital Myopathies
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07580365	Not specified	NOT_YET_RECRUITING	VirtualPark_Pediatric