BTBD18

Summary

BTBD18 (BTB domain containing 18, HGNC:37214) is a protein-coding gene on chromosome 11q12.1, encoding BTB/POZ domain-containing protein 18 (B2RXH4). Specifically required during spermatogenesis to promote expression of piRNA precursors.

Predicted to be involved in male meiosis I; piRNA transcription; and spermatogenesis. Predicted to act upstream of with a positive effect on transposable element silencing. Predicted to be active in nucleus.

Source: NCBI Gene 643376 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 99 total — 1 pathogenic
• MANE Select transcript: NM_001145101

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:37214
Approved symbol	BTBD18
Name	BTB domain containing 18
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000233436
Ensembl biotype	protein_coding
OMIM	621145
Entrez	643376

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000422652, ENST00000436147, ENST00000527995, ENST00000932237

RefSeq mRNA: 1 — MANE Select: NM_001145101 NM_001145101

CCDS: CCDS44603

Canonical transcript exons

ENST00000422652 — 3 exons

Exon	Start	End
ENSE00001613462	57751065	57751236
ENSE00001658457	57743514	57746148
ENSE00001799567	57751541	57751819

Expression profiles

Bgee: expression breadth broad, 91 present calls, max score 83.73.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.08	gold quality
bone marrow cell	CL:0002092	65.97	gold quality
colonic epithelium	UBERON:0000397	63.14	silver quality
corpus callosum	UBERON:0002336	61.16	gold quality
skeletal muscle tissue	UBERON:0001134	61.03	gold quality
bone marrow	UBERON:0002371	59.76	silver quality
sural nerve	UBERON:0015488	58.81	silver quality
muscle tissue	UBERON:0002385	57.44	silver quality
calcaneal tendon	UBERON:0003701	57.29	gold quality
right testis	UBERON:0004534	56.75	gold quality
testis	UBERON:0000473	56.24	gold quality
tonsil	UBERON:0002372	55.72	silver quality
left testis	UBERON:0004533	55.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	54.68	gold quality
adrenal tissue	UBERON:0018303	52.54	gold quality
prefrontal cortex	UBERON:0000451	50.99	gold quality
cortical plate	UBERON:0005343	49.16	gold quality
monocyte	CL:0000576	49.04	gold quality
stromal cell of endometrium	CL:0002255	48.81	gold quality
leukocyte	CL:0000738	47.96	gold quality
primary visual cortex	UBERON:0002436	47.94	silver quality
superior frontal gyrus	UBERON:0002661	47.78	gold quality
frontal cortex	UBERON:0001870	46.87	gold quality
blood	UBERON:0000178	46.30	gold quality
muscle of leg	UBERON:0001383	45.74	gold quality
cerebellum	UBERON:0002037	45.34	silver quality
cerebellar cortex	UBERON:0002129	45.14	silver quality
granulocyte	CL:0000094	45.00	silver quality
cerebellar hemisphere	UBERON:0002245	44.93	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting BTBD18, 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-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-5692A	100.00	74.40	6850
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-2467-3P	98.65	67.18	1969
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-6827-5P	98.46	64.88	1256
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-4662B	98.33	66.37	1163

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Btbd18	ENSMUSG00000086598
rattus_norvegicus	Btbd18	ENSRNOG00000043106

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359)

Protein

Protein identifiers

BTB/POZ domain-containing protein 18 — B2RXH4 (reviewed: B2RXH4)

All UniProt accessions (2): B2RXH4, E9PRF5

UniProt curated annotations — full annotation on UniProt →

Function. Specifically required during spermatogenesis to promote expression of piRNA precursors. The piRNA metabolic process mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons, which is essential for the germline integrity. Acts by facilitating transcription elongation at piRNA loci during pachytene.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_001138573* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR042915	BTBD18	Family

Pfam: PF00651

UniProt features (18 total): compositionally biased region 6, region of interest 5, modified residue 3, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-B2RXH4-F1	49.62	0.16

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 (3): 420, 671, 672

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 31 (showing top): GOBP_MALE_GAMETE_GENERATION, GOBP_ORGANELLE_FISSION, GOBP_MALE_MEIOSIS_I, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, GOBP_MEIOTIC_CELL_CYCLE, GOBP_CELL_CYCLE_PROCESS, GOBP_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, GOBP_MALE_MEIOTIC_NUCLEAR_DIVISION, GOBP_TRANSPOSITION, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOBP_MEIOSIS_I_CELL_CYCLE_PROCESS, PTEN_DN.V1_DN

GO Biological Process (6): male meiosis I (GO:0007141), spermatogenesis (GO:0007283), transposable element silencing (GO:0010526), cell differentiation (GO:0030154), positive regulation of transcription elongation by RNA polymerase II (GO:0032968), piRNA transcription (GO:0140541)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (1): nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
male gamete generation	2
meiosis I	1
male meiotic nuclear division	1
meiotic cell cycle	1
developmental process involved in reproduction	1
negative regulation of gene expression	1
retrotransposition	1
cellular developmental process	1
transcription elongation by RNA polymerase II	1
positive regulation of DNA-templated transcription, elongation	1
regulation of transcription elongation by RNA polymerase II	1
positive regulation of transcription by RNA polymerase II	1
DNA-templated transcription	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

480 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTBD18	TDRD1	Q9BXT4	462
BTBD18	SPDYC	Q5MJ68	415
BTBD18	NUP210L	Q5VU65	414
BTBD18	AGFG1	P52594	414
BTBD18	DDX50	Q9BQ39	405
BTBD18	MCMDC2	Q4G0Z9	400
BTBD18	CCDC63	Q8NA47	379
BTBD18	ADCY10	Q96PN6	379
BTBD18	MYBL1	P10243	376
BTBD18	GOLGA2	Q08379	370
BTBD18	CT45A2	Q5DJT8	370
BTBD18	KASH5	Q8N6L0	370
BTBD18	KLHL28	Q9NXS3	369
BTBD18	TNRC18	O15417	331
BTBD18	FBXO43	Q4G163	329

IntAct

4 interactions, top by confidence:

A	B	Type	Score
BTBD18	NXF1	psi-mi:“MI:0915”(physical association)	0.560
NXF1	BTBD18	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): BTBD18 (Affinity Capture-MS), BTBD18 (Two-hybrid), BTBD18 (Affinity Capture-MS), BTBD18 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0A6YY25, A6NGG8, A6X8Z5, B2RQL2, B2RXH4, D3ZMK9, D3ZUE1, E9Q7F2, O08696, O14513, P59598, P97691, Q05860, Q05AH6, Q08050, Q0GGX2, Q0VET5, Q13029, Q2M1Z3, Q3U0P1, Q571I4, Q5PSV9, Q5SSG4, Q5U2M8, Q5VV67, Q63755, Q66H04, Q68DA7, Q69ZL1, Q6DIA7, Q6JPI3, Q6P1D7, Q6PAC4, Q6PG16, Q71F56, Q76N32, Q811R2, Q86YN6, Q86YV5, Q8BJS7

Diamond homologs: A0A0A6YY25, B2RXH4, E0CZ16, E1B932, E7F6F9, F1LZ52, F1LZF0, F1MBP6, O88282, O93567, O95198, P10074, P17789, P42282, P42283, P42284, Q01295, Q1H9T6, Q24174, Q24206, Q3B7M1, Q52KG4, Q53G59, Q53HC5, Q5R633, Q5REP9, Q5U374, Q66HD2, Q6NRH0, Q7KQZ4, Q7KRI2, Q867Z4, Q86B87, Q8BGY4, Q8BZM0, Q8CA72, Q8IN81, Q8JZP3, Q8K0L9, Q8N143

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	90
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1074254	NC_000011.9:g.(?57471510)(57564464_?)del	Pathogenic

SpliceAI

347 predictions. Top by Δscore:

Variant	Effect	Δscore
11:57748397:CAA:C	donor_gain	0.9500
11:57751059:TCTTA:T	donor_loss	0.9300
11:57751060:CTTAC:C	donor_loss	0.9300
11:57751061:TTAC:T	donor_loss	0.9300
11:57751062:TA:T	donor_loss	0.9300
11:57751064:C:CA	donor_loss	0.9300
11:57746146:CAC:C	acceptor_gain	0.9200
11:57746149:C:CC	acceptor_gain	0.9200
11:57751131:C:G	donor_gain	0.9100
11:57751180:A:T	donor_gain	0.9100
11:57746148:CCTGA:C	acceptor_loss	0.9000
11:57746149:C:G	acceptor_loss	0.9000
11:57751064:CCTT:C	donor_gain	0.8900
11:57746144:CTCAC:C	acceptor_gain	0.8700
11:57751065:C:A	donor_loss	0.8400
11:57751194:C:T	donor_gain	0.8400
11:57746145:TCAC:T	acceptor_gain	0.8200
11:57746146:CACC:C	acceptor_gain	0.8200
11:57748806:ATT:A	donor_gain	0.8200
11:57751133:A:T	donor_gain	0.8200
11:57751247:G:GT	donor_gain	0.8100
11:57746145:TCACC:T	acceptor_gain	0.7900
11:57746900:G:C	donor_gain	0.7600
11:57748396:A:AC	donor_gain	0.7600
11:57748397:C:CC	donor_gain	0.7600
11:57748450:CAA:C	donor_gain	0.7600
11:57748451:AAA:A	donor_gain	0.7600
11:57746151:G:C	acceptor_loss	0.7500
11:57749124:G:GT	donor_gain	0.7400
11:57749668:TGA:T	donor_gain	0.6800

AlphaMissense

4599 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:57745168:A:G	W369R	0.998
11:57745168:A:T	W369R	0.998
11:57746105:G:C	S56R	0.998
11:57746105:G:T	S56R	0.998
11:57746107:T:G	S56R	0.998
11:57745166:C:A	W369C	0.996
11:57745166:C:G	W369C	0.996
11:57745194:A:G	L360P	0.995
11:57746097:A:G	F59S	0.995
11:57746133:G:T	A47D	0.995
11:57745938:G:T	A112D	0.994
11:57745194:A:T	L360H	0.993
11:57746139:A:T	V45D	0.991
11:57745167:C:G	W369S	0.990
11:57745929:A:G	L115P	0.990
11:57746118:A:T	L52Q	0.990
11:57751118:A:G	L24P	0.990
11:57745200:A:T	V358D	0.989
11:57746016:A:T	L86H	0.989
11:57746118:A:G	L52P	0.989
11:57751076:A:G	L38P	0.989
11:57745939:C:G	A112P	0.988
11:57745997:G:C	F92L	0.988
11:57745997:G:T	F92L	0.988
11:57745999:A:G	F92L	0.988
11:57746007:A:G	L89P	0.988
11:57746129:G:C	H48Q	0.988
11:57746129:G:T	H48Q	0.988
11:57751076:A:T	L38Q	0.988
11:57745884:A:G	L130S	0.986

dbSNP variants (sampled 300 via entrez): RS1000137260 (11:57753966 G>A), RS1000208250 (11:57751589 C>T), RS1000259235 (11:57751859 G>A,T), RS1000328985 (11:57752116 AC>A,ACC), RS1000483658 (11:57744895 C>G), RS1000739039 (11:57752974 C>A,G), RS1000779868 (11:57746511 G>A), RS1000803936 (11:57751429 C>G), RS1001338399 (11:57753196 C>A,G), RS1001896352 (11:57753135 G>A), RS1001950343 (11:57753342 A>C), RS1002252301 (11:57752759 G>A), RS1002340299 (11:57746180 G>C), RS1002709607 (11:57752407 G>A), RS1003300794 (11:57750618 A>C)

Disease associations

OMIM: gene MIM:621145 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002539_6	Schizophrenia	2.000000e-09
GCST004521_290	Autism spectrum disorder or schizophrenia	5.000000e-08
GCST005232_71	Neuroticism	7.000000e-11
GCST006803_71	Schizophrenia	1.000000e-09
GCST009600_99	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
aflatoxin B2	decreases methylation	1
2-palmitoylglycerol	increases expression	1
bisphenol S	decreases methylation	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Estradiol	affects cotreatment, decreases expression	1
Lead	increases expression	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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