TOP6BL

Summary

TOP6BL (TOP6B like initiator of meiotic double strand breaks, HGNC:26197) is a protein-coding gene on chromosome 11q13.2, encoding Type 2 DNA topoisomerase 6 subunit B-like (Q8N6T0). Component of a topoisomerase 6 complex specifically required for meiotic recombination.

Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm.

Source: NCBI Gene 79703 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hydatidiform mole, recurrent, 4 (Limited, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 38 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• MANE Select transcript: NM_001302084

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26197
Approved symbol	TOP6BL
Name	TOP6B like initiator of meiotic double strand breaks
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22531, TOPOVIBL
Ensembl gene	ENSG00000173715
Ensembl biotype	protein_coding
OMIM	616109
Entrez	79703

Gene structure

Transcript identifiers

Ensembl transcripts: 83 — 75 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000524551, ENST00000525449, ENST00000525908, ENST00000526260, ENST00000526270, ENST00000526718, ENST00000527352, ENST00000527368, ENST00000527634, ENST00000531400, ENST00000531415, ENST00000532089, ENST00000532565, ENST00000532727, ENST00000533143, ENST00000534325, ENST00000540737, ENST00000642265, ENST00000901148, ENST00000901149, ENST00000901150, ENST00000901151, ENST00000901152, ENST00000901153, ENST00000901154, ENST00000901155, ENST00000901156, ENST00000901157, ENST00000901158, ENST00000901159, ENST00000901160, ENST00000901161, ENST00000901162, ENST00000901163, ENST00000901164, ENST00000901165, ENST00000901166, ENST00000901167, ENST00000901168, ENST00000901169, ENST00000901170, ENST00000901171, ENST00000901172, ENST00000901173, ENST00000901174, ENST00000901175, ENST00000901176, ENST00000901177, ENST00000901178, ENST00000901179, ENST00000901180, ENST00000901181, ENST00000901182, ENST00000914048, ENST00000914049, ENST00000914050, ENST00000914051, ENST00000914052, ENST00000914053, ENST00000914054, ENST00000914055, ENST00000914056, ENST00000914057, ENST00000914058, ENST00000914059, ENST00000914060, ENST00000914061, ENST00000914062, ENST00000914063, ENST00000914064, ENST00000945062, ENST00000945063, ENST00000945064, ENST00000945065, ENST00000945066, ENST00000945067, ENST00000945068, ENST00000945069, ENST00000945070, ENST00000945071, ENST00000945072, ENST00000945073, ENST00000945074

RefSeq mRNA: 2 — MANE Select: NM_001302084 NM_001302084, NM_024650

CCDS: CCDS76440

Canonical transcript exons

ENST00000540737 — 15 exons

Exon	Start	End
ENSE00001187797	66813865	66814015
ENSE00001187798	66803995	66804190
ENSE00002155412	66838370	66838445
ENSE00002171354	66744769	66744919
ENSE00002186366	66843169	66843516
ENSE00003495518	66842849	66843069
ENSE00003497997	66800641	66800696
ENSE00003518765	66821643	66821764
ENSE00003537186	66796281	66796364
ENSE00003573036	66759043	66759096
ENSE00003586163	66801031	66801102
ENSE00003589251	66822564	66822674
ENSE00003616970	66816053	66816199
ENSE00003636305	66828266	66828364
ENSE00003672753	66788160	66788269

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 95.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9140 / max 75.6471, expressed in 1615 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115370	5.7369	1540
115371	2.1718	905
115372	0.0053	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	95.95	gold quality
skin of leg	UBERON:0001511	94.65	gold quality
lower esophagus mucosa	UBERON:0035834	93.47	gold quality
cerebellar hemisphere	UBERON:0002245	93.25	gold quality
cerebellar cortex	UBERON:0002129	93.12	gold quality
metanephros cortex	UBERON:0010533	93.04	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.84	gold quality
right testis	UBERON:0004534	92.42	gold quality
left testis	UBERON:0004533	91.87	gold quality
zone of skin	UBERON:0000014	91.53	gold quality
esophagus mucosa	UBERON:0002469	91.34	gold quality
cortical plate	UBERON:0005343	90.55	gold quality
cerebellum	UBERON:0002037	90.16	gold quality
ganglionic eminence	UBERON:0004023	89.27	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.17	gold quality
mucosa of transverse colon	UBERON:0004991	89.13	gold quality
minor salivary gland	UBERON:0001830	89.04	gold quality
testis	UBERON:0000473	88.88	gold quality
right adrenal gland cortex	UBERON:0035827	87.50	gold quality
right uterine tube	UBERON:0001302	87.45	gold quality
endometrium epithelium	UBERON:0004811	87.42	gold quality
mouth mucosa	UBERON:0003729	87.11	gold quality
granulocyte	CL:0000094	87.09	gold quality
small intestine	UBERON:0002108	86.90	gold quality
rectum	UBERON:0001052	86.82	gold quality
adenohypophysis	UBERON:0002196	86.80	gold quality
right adrenal gland	UBERON:0001233	86.69	gold quality
saliva-secreting gland	UBERON:0001044	86.21	gold quality
left adrenal gland cortex	UBERON:0035825	86.11	gold quality
transverse colon	UBERON:0001157	85.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	38.27
E-ANND-3	yes	9.99
E-MTAB-6379	no	25.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting TOP6BL, 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-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7108-3P	94.37	64.79	183

Literature-anchored findings (GeneRIF, showing 1)

• Top association findings suggested that the bipolar disorder risk allele at SNP rs10896235 in C11orf80 may be associated with increased risk of headache, including migraine. (PMID:27529678)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:195212	ENSDARG00000075203
mus_musculus	Top6bl	ENSMUSG00000071691
rattus_norvegicus	Top6bl	ENSRNOG00000026579

Protein

Protein identifiers

Type 2 DNA topoisomerase 6 subunit B-like — Q8N6T0 (reviewed: Q8N6T0)

Alternative names: TOP6B like initiator of meiotic double strand breaks, Type 2 DNA topoisomerase VI subunit B-like

All UniProt accessions (12): Q8N6T0, A0A140TA08, A0A2R8Y5A2, A0A2U3TZP7, E9PJS1, E9PKM2, E9PMI8, E9PMU2, H0YD22, H0YD55, H0YDL3, H0YE21

UniProt curated annotations — full annotation on UniProt →

Function. Component of a topoisomerase 6 complex specifically required for meiotic recombination. Together with SPO11, mediates DNA cleavage that forms the double-strand breaks (DSB) that initiate meiotic recombination. The complex promotes relaxation of negative and positive supercoiled DNA and DNA decatenation through cleavage and ligation cycles.

Subunit / interactions. Heterotetramer of SPO11 and 2 TOP6BL chains. Interacts with SPO11.

Subcellular location. Chromosome.

Tissue specificity. Detected in lung, spleen,colon and in skeletal muscle. Expressed in the ovaries, Fallopian tubes and uterus.

Disease relevance. Hydatidiform mole, recurrent, 4 (HYDM4) [MIM:618432] A disorder characterized by excessive trophoblast development that produces a growing mass of tissue inside the uterus at the beginning of a pregnancy. It leads to abnormal pregnancies with no embryo, and cystic degeneration of the chorionic villi. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. Despite a weak sequence similarity, retains most of the structural features of the ancestral archaeal Top6B subunit (AC O05207), including the transducer domain that interacts with the SPO11 subunit and the ATP-binding fold, also named GHKL fold.

Miscellaneous. Expansion of a polymorphic CGG repeat within the 5’-UTR of this gene may be the cause of folate-sensitive fragile site FRA11A. The expansion is identified in the 15-year-old proband with intellectual disability as well as in phenotypically normal members of the family. Contains a signal peptide sequence at position 1-23.

Similarity. Belongs to the TOP6B-like family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N6T0-6	4	yes
Q8N6T0-1	3
Q8N6T0-4	1
Q8N6T0-5	2

RefSeq proteins (2): NP_001289013, NP_078926 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028040	TopoVIB-like	Family

Pfam: PF15091

UniProt features (11 total): splice variant 5, compositionally biased region 3, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6T0-F1	68.14	0.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 87 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GGGTGGRR_PAX4_03, CHANDRAN_METASTASIS_DN, chr11q13, GOBP_ORGANELLE_FISSION, NIKOLSKY_BREAST_CANCER_11Q12_Q14_AMPLICON, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, MODULE_48, MODULE_95, GOBP_MEIOTIC_CELL_CYCLE, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOBP_CELL_CYCLE_PROCESS, GOBP_DNA_METABOLIC_PROCESS, GOBP_DNA_RECOMBINATION

GO Biological Process (3): reciprocal meiotic recombination (GO:0007131), meiotic DNA double-strand break formation (GO:0042138), meiotic cell cycle (GO:0051321)

GO Molecular Function (0):

GO Cellular Component (1): chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiosis I	1
reciprocal homologous recombination	1
meiotic cell cycle process	1
DNA metabolic process	1
meiosis I cell cycle process	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TOP6BL	SPO11	Q9Y5K1	986
TOP6BL	REC114	Q7Z4M0	824
TOP6BL	IHO1	Q8IYA8	800
TOP6BL	MEI1	Q5TIA1	712
TOP6BL	ANKRD31	Q8N7Z5	636
TOP6BL	MEI4	A8MW99	621
TOP6BL	PRDM9	Q9NQV7	592
TOP6BL	HORMAD1	Q86X24	530
TOP6BL	CCDC188	H7C350	507
TOP6BL	OR4N5	Q8IXE1	446
TOP6BL	SPATA31A6	Q5VVP1	436
TOP6BL	SYCP1	Q15431	425
TOP6BL	OR4K14	Q8NGD5	419
TOP6BL	KHDC3L	Q587J8	417
TOP6BL	SYCP3	Q8IZU3	405

IntAct

0 interactions, top by confidence:

BioGRID (2): C11orf80 (Affinity Capture-MS), C11orf80 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0D9SF12, A2A8T7, A6H7E2, A6NF36, A6NFA0, A6NI87, E1C7U0, P03246, P03247, P0DO92, P14355, P14683, Q0VG49, Q1HVF6, Q32LN6, Q3KPU7, Q3KSS3, Q4V7D2, Q4ZG55, Q5DU28, Q5JX69, Q5JX71, Q5R7E2, Q5U4U4, Q642A3, Q6NRW0, Q6P1U0, Q6P4J6, Q6P9N1, Q6PEX7, Q6X4T0, Q7L3B6, Q7SYV9, Q7T346, Q80Y73, Q8BJS8, Q8CF25, Q8IWB6, Q8N6T0, Q8NCU1

Diamond homologs: J3QMY9, Q8N6T0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	9
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
4277340	NM_001302084.2(TOP6BL):c.25+1G>C	Pathogenic
2571602	NM_001302084.2(TOP6BL):c.1273_1274del (p.Lys425fs)	Likely pathogenic

SpliceAI

3966 predictions. Top by Δscore:

Variant	Effect	Δscore
11:66745072:G:GT	donor_gain	1.0000
11:66759027:ATTCT:A	acceptor_gain	1.0000
11:66759031:T:TA	acceptor_gain	1.0000
11:66759038:TACA:T	acceptor_loss	1.0000
11:66759040:CA:C	acceptor_loss	1.0000
11:66759041:A:AG	acceptor_gain	1.0000
11:66759041:A:AT	acceptor_loss	1.0000
11:66759041:AGTT:A	acceptor_gain	1.0000
11:66759042:G:A	acceptor_loss	1.0000
11:66759042:G:GA	acceptor_gain	1.0000
11:66759042:GT:G	acceptor_gain	1.0000
11:66759042:GTT:G	acceptor_gain	1.0000
11:66759042:GTTG:G	acceptor_gain	1.0000
11:66759092:AAAAG:A	donor_loss	1.0000
11:66759093:AAAGG:A	donor_loss	1.0000
11:66759096:GGTA:G	donor_loss	1.0000
11:66759097:G:T	donor_loss	1.0000
11:66759098:T:A	donor_loss	1.0000
11:66800636:TGCA:T	acceptor_loss	1.0000
11:66800638:CAGG:C	acceptor_loss	1.0000
11:66800640:G:A	acceptor_loss	1.0000
11:66800640:GGTCA:G	acceptor_gain	1.0000
11:66816049:CTA:C	acceptor_loss	1.0000
11:66816051:A:AG	acceptor_gain	1.0000
11:66816052:G:GG	acceptor_gain	1.0000
11:66816052:GAT:G	acceptor_gain	1.0000
11:66816052:GATT:G	acceptor_gain	1.0000
11:66816052:GATTT:G	acceptor_gain	1.0000
11:66816195:CTGGG:C	donor_gain	1.0000
11:66816196:TGGG:T	donor_gain	1.0000

AlphaMissense

3367 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:66822630:A:C	S409R	0.985
11:66822632:C:A	S409R	0.985
11:66822632:C:G	S409R	0.985
11:66822645:T:C	F414L	0.978
11:66822647:C:A	F414L	0.978
11:66822647:C:G	F414L	0.978
11:66804131:G:C	A227P	0.972
11:66822657:T:C	C418R	0.962
11:66822646:T:C	F414S	0.955
11:66804132:C:A	A227E	0.950
11:66822646:T:G	F414C	0.948
11:66813868:T:C	F248L	0.945
11:66813870:T:A	F248L	0.945
11:66813870:T:G	F248L	0.945
11:66822598:C:A	A398D	0.945
11:66822649:G:C	R415P	0.945
11:66813866:T:A	I247K	0.942
11:66828297:T:C	L434P	0.942
11:66813877:G:A	G251R	0.939
11:66813877:G:C	G251R	0.939
11:66804125:G:C	A225P	0.938
11:66828285:T:C	F430S	0.937
11:66804129:C:A	A226D	0.935
11:66804117:T:C	L222P	0.929
11:66813890:T:C	L255P	0.929
11:66804128:G:C	A226P	0.928
11:66816140:T:C	L326P	0.927
11:66816160:T:C	F333L	0.927
11:66816162:C:A	F333L	0.927
11:66816162:C:G	F333L	0.927

dbSNP variants (sampled 300 via entrez): RS1000004593 (11:66828059 A>G), RS1000079174 (11:66765973 A>T), RS1000126271 (11:66752442 C>G,T), RS1000154215 (11:66758515 C>T), RS1000154934 (11:66804631 G>A), RS1000155126 (11:66787810 A>G), RS1000179131 (11:66832277 T>A), RS1000243760 (11:66784382 A>G), RS1000332827 (11:66838523 T>C), RS1000354248 (11:66791255 T>G), RS1000366628 (11:66746253 G>C), RS1000376178 (11:66772836 C>A,G), RS1000387586 (11:66752135 T>C,G), RS1000401341 (11:66784175 C>T), RS1000403870 (11:66804791 G>T)

Disease associations

OMIM: gene MIM:616109 | disease phenotypes: MIM:618432, MIM:620547

GenCC curated gene-disease

Disease	Classification	Inheritance
hydatidiform mole, recurrent, 4	Limited	Autosomal recessive

Mondo (2): hydatidiform mole, recurrent, 4 (MONDO:0032747), spermatogenic failure 88 (MONDO:0957821)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0008222	Female infertility
HP:0032192	Hydatidiform mole
HP:0200067	Recurrent spontaneous abortion

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001241_12	Bipolar disorder	2.000000e-07
GCST004139_3	Bipolar disorder	1.000000e-07
GCST005993_53	Mean corpuscular hemoglobin	3.000000e-09
GCST006097_12	Moderate to vigorous physical activity levels	6.000000e-10
GCST008103_30	Bipolar disorder	4.000000e-08
GCST008972_104	Urate levels	2.000000e-120
GCST010512_23	Serum uric acid levels	1.000000e-14
GCST012227_668	Hip circumference adjusted for BMI	4.000000e-13
GCST90020028_1913	Hip circumference adjusted for BMI	4.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0008002	physical activity measurement
EFO:0004531	urate measurement
EFO:0004761	uric acid measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Valproic Acid	decreases expression	2
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
pentanal	decreases expression	1
Irinotecan	increases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1
Cadmium	increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1
tert-Butylhydroperoxide	decreases expression	1

Clinical trials (associated diseases)

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