PIWIL3

Summary

PIWIL3 (piwi like RNA-mediated gene silencing 3, HGNC:18443) is a protein-coding gene on chromosome 22q11.23, encoding Piwi-like protein 3 (Q7Z3Z3). May play a role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity.

This gene encodes a member of the PIWI subfamily of Argonaute family proteins. This subfamily of proteins contains a PAZ domain, found in proteins involved in RNA-mediated gene silencing, and a C-terminal Piwi domain. The encoded protein is thought to function in maintenance of germline cells. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 440822 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 159 total
• MANE Select transcript: NM_001255975

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18443
Approved symbol	PIWIL3
Name	piwi like RNA-mediated gene silencing 3
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Aliases	HIWI3
Ensembl gene	ENSG00000184571
Ensembl biotype	protein_coding
OMIM	610314
Entrez	440822

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 nonsense_mediated_decay

ENST00000332271, ENST00000527701, ENST00000533313, ENST00000616349

RefSeq mRNA: 2 — MANE Select: NM_001255975 NM_001008496, NM_001255975

CCDS: CCDS33623, CCDS93133

Canonical transcript exons

ENST00000616349 — 21 exons

Exon	Start	End
ENSE00001320568	24719034	24719588
ENSE00002191118	24774322	24774720
ENSE00003467975	24728177	24728374
ENSE00003476830	24719748	24719895
ENSE00003483492	24759869	24759989
ENSE00003491438	24749693	24749819
ENSE00003494150	24727950	24728053
ENSE00003506230	24755784	24755905
ENSE00003539030	24723130	24723255
ENSE00003565058	24735708	24735892
ENSE00003581412	24748907	24749021
ENSE00003584845	24756491	24756705
ENSE00003612850	24724887	24725037
ENSE00003622986	24734084	24734156
ENSE00003623271	24757908	24758039
ENSE00003636552	24751387	24751498
ENSE00003645310	24749404	24749521
ENSE00003652882	24754014	24754217
ENSE00003661066	24754784	24754864
ENSE00003676971	24725445	24725515
ENSE00003931535	24762398	24762521

Expression profiles

Bgee: expression breadth tissue_specific, 8 present calls, max score 79.55.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.55	gold quality
sural nerve	UBERON:0015488	44.35	gold quality
granulocyte	CL:0000094	39.08	gold quality
ganglionic eminence	UBERON:0004023	38.90	gold quality
bone marrow cell	CL:0002092	38.31	gold quality
testis	UBERON:0000473	38.23	gold quality
placenta	UBERON:0001987	37.70	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
right testis	UBERON:0004534	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow	UBERON:0002371	36.23	gold quality
leukocyte	CL:0000738	35.24	gold quality
skeletal muscle tissue	UBERON:0001134	34.84	gold quality
monocyte	CL:0000576	34.76	gold quality
apex of heart	UBERON:0002098	34.51	gold quality
left testis	UBERON:0004533	34.32	silver quality
cortex of kidney	UBERON:0001225	33.57	gold quality
urinary bladder	UBERON:0001255	33.49	gold quality
duodenum	UBERON:0002114	32.45	gold quality
mucosa of stomach	UBERON:0001199	32.27	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
muscle tissue	UBERON:0002385	32.13	gold quality
liver	UBERON:0002107	31.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	31.66	gold quality
prefrontal cortex	UBERON:0000451	31.20	gold quality
lymph node	UBERON:0000029	31.15	gold quality
right adrenal gland cortex	UBERON:0035827	30.45	gold quality
ectocervix	UBERON:0012249	30.32	gold quality
islet of Langerhans	UBERON:0000006	29.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting PIWIL3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6745	99.74	65.33	1321

Literature-anchored findings (GeneRIF, showing 5)

• PIWIL3 proteins were expressed in the cytoplasma of human astrocytic glioma and meningioma. (PMID:18616918)
• individuals with HIWI3 non-synonymous rs11703684 variant genotypes exhibited a significantly reduced oligozoospermia risk (PMID:20940137)
• Our data indicate that PIWIL3 protein expression is elevated in more aggressive primary malignant melanoma(MM )and metastatic disease. As also observed in other malignancies, PIWIL3 seems to play a role in MM progression. (PMID:27858163)
• overexpression of Piwil3 promotes the proliferation, migration and invasion of GC cells partially through JAK2/STAT3 signal pathway. (PMID:28869440)
• PIWIL3 was also a target of CEBPA, forming a positive feedback loop in the growth regulation of glioma cells. Significantly, knockdown of OIP5-AS1 combined with over-expression of PIWIL3 and miR-367-3p resulted in tumor regression and extended survival in vivo. (PMID:29464001)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	piwil1	ENSDARG00000041699
drosophila_melanogaster	aub	FBGN0000146
drosophila_melanogaster	piwi	FBGN0004872
caenorhabditis_elegans	prg-1	WBGENE00004178

Paralogs (3): PIWIL1 (ENSG00000125207), PIWIL4 (ENSG00000134627), PIWIL2 (ENSG00000197181)

Protein

Protein identifiers

Piwi-like protein 3 — Q7Z3Z3 (reviewed: Q7Z3Z3)

All UniProt accessions (4): Q7Z3Z3, A0A8J9G8U8, E9PIP6, E9PJG9

UniProt curated annotations — full annotation on UniProt →

Function. May play a role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and govern the methylation and subsequent repression of transposons. Directly binds piRNAs, a class of 24 to 30 nucleotide RNAs that are generated by a Dicer-independent mechanism and are primarily derived from transposons and other repeated sequence elements. Besides their function in transposable elements repression, piRNAs are probably involved in other processes during meiosis such as translation regulation.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in testis.

Similarity. Belongs to the argonaute family. Piwi subfamily.

RefSeq proteins (2): NP_001008496, NP_001242904* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003100	PAZ_dom	Domain
IPR003165	Piwi	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR036085	PAZ_dom_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily

Pfam: PF02170, PF02171, PF23278

UniProt features (12 total): sequence variant 6, domain 2, compositionally biased region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z3Z3-F1	83.91	0.64

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 48 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, KEGG_DORSO_VENTRAL_AXIS_FORMATION, GOBP_MALE_GAMETE_GENERATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_PIRNA_PROCESSING, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MEIOTIC_CELL_CYCLE, GOBP_REGULATION_OF_TRANSLATION, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOCC_POLE_PLASM, GOBP_REGULATION_OF_PROTEIN_METABOLIC_PROCESS

GO Biological Process (7): regulation of translation (GO:0006417), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), regulatory ncRNA-mediated gene silencing (GO:0031047), piRNA processing (GO:0034587), meiotic cell cycle (GO:0051321), spermatid development (GO:0007286)

GO Molecular Function (9): RNA endonuclease activity (GO:0004521), piRNA binding (GO:0034584), nucleic acid binding (GO:0003676), RNA binding (GO:0003723), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), P granule (GO:0043186)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
negative regulation of gene expression	1
regulatory ncRNA processing	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
germ cell development	1
spermatid differentiation	1
endonuclease activity	1
RNA nuclease activity	1
regulatory RNA binding	1
nucleic acid binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasmic ribonucleoprotein granule	1
germ plasm	1

Protein interactions and networks

STRING

580 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PIWIL3	DICER1	Q9UPY3	768
PIWIL3	HENMT1	Q5T8I9	603
PIWIL3	TDRD9	Q8NDG6	603
PIWIL3	PIR	O00625	597
PIWIL3	PIWIL2	Q8TC59	589
PIWIL3	PLD6	Q8N2A8	581
PIWIL3	TDRD5	Q8NAT2	560
PIWIL3	TDRKH	Q9Y2W6	554
PIWIL3	TDRD15	B5MCY1	504
PIWIL3	MOV10L1	Q9BXT6	502
PIWIL3	TDRD7	Q8NHU6	481
PIWIL3	TDRD1	Q9BXT4	462
PIWIL3	ALG1	Q9BT22	462
PIWIL3	MAEL	Q96JY0	460
PIWIL3	PIWIL1	Q96J94	432

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ATG16L1		psi-mi:“MI:0914”(association)	0.350

BioGRID (7): PIWIL3 (Affinity Capture-MS), PIWIL3 (Affinity Capture-Western), PIWIL3 (Affinity Capture-MS), PIWIL3 (Cross-Linking-MS (XL-MS)), PIWIL3 (Cross-Linking-MS (XL-MS)), PIWIL3 (Cross-Linking-MS (XL-MS)), PIWIL3 (Protein-RNA)

ESM2 similar proteins: A2CEI6, A3KPK0, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O04379, O48771, O76922, O77503, O89040, Q0JF58, Q4G033, Q4KLV6, Q5NBN9, Q5Z5B2, Q5ZLG4, Q5ZMW0, Q69VD5, Q6DCX2, Q6DJB9, Q6EU14, Q6K972, Q6QME8, Q6T5B7, Q6YSJ5, Q6Z4F1, Q7PLK0, Q7XSA2, Q7Y001, Q7Z3Z3, Q7Z3Z4, Q84VQ0, Q851R2, Q8CDG1, Q8CGT6, Q8CJF8, Q8CJF9, Q8CJG0, Q8CJG1

Diamond homologs: A2CEI6, A6N7Y9, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O76922, Q4G033, Q7PLK0, Q7Z3Z3, Q7Z3Z4, Q8CDG1, Q8CGT6, Q8TC59, Q8UVX0, Q96J94, Q9JMB7, Q9VKM1, O61931, Q2PC95, Q09249, Q21770, P34681, Q7XTS3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	134
Likely benign	11
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3336 predictions. Top by Δscore:

Variant	Effect	Δscore
22:24719587:CCCTT:C	acceptor_gain	1.0000
22:24719588:CCTT:C	acceptor_gain	1.0000
22:24719591:T:C	acceptor_gain	1.0000
22:24719747:CTGG:C	donor_gain	1.0000
22:24724884:TACTT:T	donor_loss	1.0000
22:24724885:A:AC	donor_gain	1.0000
22:24724886:C:CA	donor_loss	1.0000
22:24724886:C:CC	donor_gain	1.0000
22:24725035:CAG:C	acceptor_gain	1.0000
22:24725038:C:CC	acceptor_gain	1.0000
22:24725050:C:CT	acceptor_gain	1.0000
22:24725051:A:T	acceptor_gain	1.0000
22:24725514:ACCTG:A	acceptor_loss	1.0000
22:24725515:CCT:C	acceptor_loss	1.0000
22:24725517:T:A	acceptor_loss	1.0000
22:24728061:T:C	acceptor_gain	1.0000
22:24728061:T:TC	acceptor_gain	1.0000
22:24728067:T:C	acceptor_gain	1.0000
22:24728067:T:TC	acceptor_gain	1.0000
22:24728756:AAG:A	donor_gain	1.0000
22:24735706:A:AC	donor_gain	1.0000
22:24735707:C:CC	donor_gain	1.0000
22:24735707:CATTT:C	donor_gain	1.0000
22:24749019:TTA:T	acceptor_gain	1.0000
22:24749022:C:CC	acceptor_gain	1.0000
22:24751381:TCATA:T	donor_loss	1.0000
22:24751382:CATA:C	donor_loss	1.0000
22:24751385:A:AC	donor_gain	1.0000
22:24751386:C:CC	donor_gain	1.0000
22:24751386:C:CT	donor_loss	1.0000

AlphaMissense

5768 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:24719562:G:C	C853W	0.999
22:24719769:G:C	C837W	0.999
22:24719770:C:T	C837Y	0.999
22:24724977:C:G	R723P	0.999
22:24727970:A:C	S672R	0.999
22:24727970:A:T	S672R	0.999
22:24727972:T:G	S672R	0.999
22:24719563:C:T	C853Y	0.998
22:24719572:G:T	P850Q	0.998
22:24719837:A:C	Y815D	0.998
22:24719874:A:C	S802R	0.998
22:24719874:A:T	S802R	0.998
22:24719876:T:G	S802R	0.998
22:24719886:A:C	F798L	0.998
22:24719886:A:T	F798L	0.998
22:24719888:A:G	F798L	0.998
22:24724981:A:C	Y722D	0.998
22:24727975:C:G	A671P	0.998
22:24728210:C:A	K633N	0.998
22:24728210:C:G	K633N	0.998
22:24728229:G:T	A627D	0.998
22:24728291:G:C	S606R	0.998
22:24728291:G:T	S606R	0.998
22:24728293:T:G	S606R	0.998
22:24719572:G:C	P850R	0.997
22:24723226:T:A	K763I	0.997
22:24724971:C:T	G725E	0.997
22:24727977:A:T	V670D	0.997
22:24728194:A:G	W639R	0.997
22:24728194:A:T	W639R	0.997

dbSNP variants (sampled 300 via entrez): RS1000066715 (22:24720044 TAAAC>T), RS1000094730 (22:24742917 C>G), RS1000100426 (22:24773300 C>T), RS1000162250 (22:24761783 T>C,G), RS1000226429 (22:24762136 C>G), RS1000228458 (22:24740084 T>G), RS1000228548 (22:24720267 T>G), RS1000237805 (22:24722451 A>C), RS1000250626 (22:24728476 T>C), RS1000326137 (22:24774908 C>G), RS1000432920 (22:24769280 C>A,T), RS1000452882 (22:24772941 C>T), RS1000582331 (22:24769502 C>G,T), RS1000599040 (22:24731592 A>C), RS1000662490 (22:24767486 G>A)

Disease associations

OMIM: gene MIM:610314 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002481_6	Acne (severe)	6.000000e-07
GCST003542_202	Night sleep phenotypes	3.000000e-06
GCST008821_7	Neurofibrillary tangles	8.000000e-06
GCST90013407_122	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-104

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006797	neurofibrillary tangles measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
CGP 52608	affects binding, increases reaction	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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