GNB1L

Summary

GNB1L (G protein subunit beta 1 like, HGNC:4397) is a protein-coding gene on chromosome 22q11.21, encoding Guanine nucleotide-binding protein subunit beta-like protein 1 (Q9BYB4). Acts as a critical regulator of DNA damage response (DDR) signaling via specifically regulating phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. It is a selective cancer dependency (DepMap: 84.7% of cell lines).

This gene encodes a G-protein beta-subunit-like polypeptide which is a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 6 WD repeats and is highly expressed in the heart. The gene maps to the region on chromosome 22q11, which is deleted in DiGeorge syndrome, trisomic in derivative 22 syndrome and tetrasomic in cat-eye syndrome. Therefore, this gene may contribute to the etiology of those disorders. Transcripts from this gene share exons with some transcripts from the C22orf29 gene.

Source: NCBI Gene 54584 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 107 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 84.7% of screened cell lines
• MANE Select transcript: NM_053004

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4397
Approved symbol	GNB1L
Name	G protein subunit beta 1 like
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	GY2, WDR14
Ensembl gene	ENSG00000185838
Ensembl biotype	protein_coding
OMIM	610778
Entrez	54584

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000329517, ENST00000403325, ENST00000405009, ENST00000453108, ENST00000460402, ENST00000481086, ENST00000879065

RefSeq mRNA: 1 — MANE Select: NM_053004 NM_053004

CCDS: CCDS13768

Canonical transcript exons

ENST00000329517 — 8 exons

Exon	Start	End
ENSE00001297632	19821228	19821375
ENSE00001318823	19820598	19820723
ENSE00001321538	19783223	19788960
ENSE00003466940	19812285	19812447
ENSE00003554940	19806659	19806757
ENSE00003627395	19802001	19802216
ENSE00003693672	19854443	19854539
ENSE00003849786	19854820	19854874

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 90.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.8977 / max 216.6662, expressed in 1735 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193167	11.8977	1735
193166	11.0144	1741

Top tissues by expression

268 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	90.36	gold quality
stromal cell of endometrium	CL:0002255	78.84	gold quality
granulocyte	CL:0000094	77.93	gold quality
oocyte	CL:0000023	77.23	gold quality
mucosa of transverse colon	UBERON:0004991	76.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.23	gold quality
cortical plate	UBERON:0005343	76.15	gold quality
cervix squamous epithelium	UBERON:0006922	76.07	gold quality
prefrontal cortex	UBERON:0000451	75.90	gold quality
right frontal lobe	UBERON:0002810	75.40	gold quality
skin of leg	UBERON:0001511	75.36	gold quality
skin of abdomen	UBERON:0001416	75.06	gold quality
lower esophagus mucosa	UBERON:0035834	74.89	gold quality
endothelial cell	CL:0000115	74.56	gold quality
ventricular zone	UBERON:0003053	74.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.37	gold quality
anterior cingulate cortex	UBERON:0009835	74.36	gold quality
cingulate cortex	UBERON:0003027	74.33	gold quality
blood	UBERON:0000178	74.06	gold quality
buccal mucosa cell	CL:0002336	73.98	gold quality
spleen	UBERON:0002106	73.90	gold quality
zone of skin	UBERON:0000014	73.61	gold quality
popliteal artery	UBERON:0002250	73.55	gold quality
tibial artery	UBERON:0007610	73.54	gold quality
ectocervix	UBERON:0012249	73.47	gold quality
gastrocnemius	UBERON:0001388	73.46	gold quality
embryo	UBERON:0000922	73.43	gold quality
frontal cortex	UBERON:0001870	73.41	gold quality
neocortex	UBERON:0001950	73.40	gold quality
ganglionic eminence	UBERON:0004023	73.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, NFKB, TP53, TP73

miRNA regulators (miRDB)

5 targeting GNB1L, 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-3688-3P	99.97	72.02	2834
HSA-MIR-8060	98.61	66.93	1187
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-1247-3P	83.69	63.18	99

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 84.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• markers associated with psychosis are also correlated with alterations in GNB1L expression, raising the hypothesis that the risk to develop psychosis at this locus could be mediated in a dose sensitive manner via gene expression (PMID:18003636)
• GbetaL is involved in the negative regulation of TNFalpha-stimulated NF-kappaB signaling through a direct interaction with IKK. (PMID:18755269)
• The present findings support assertions that GNB1L is one of the genes in the 22q11DS region responsible for increasing the risk of schizophrenia. (PMID:19011233)
• The results of this study suggested that GNB1L is linked with bipolar disorder and schizophrenia and not with major depressive disorder. (PMID:20538345)
• Beta-blocker therapy and heart rate control during exercise testing in the general population: role of GNB1L variant. (PMID:20860462)
• mRNA expression results implies that the GNB1L high-expression allele is the risk allele for schizophrenia and bipolar disorder in the Han Chinese population. (PMID:24831436)
• Sequencing of the coding regions of GNBIL on chromosome 22q11.2 as a risk gene of schizophrenia. (PMID:33932639)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnb1l	ENSDARG00000036293
mus_musculus	Gnb1l	ENSMUSG00000000884
rattus_norvegicus	Gnb1l	ENSRNOG00000001891

Paralogs (1): TBL3 (ENSG00000183751)

Protein

Protein identifiers

Guanine nucleotide-binding protein subunit beta-like protein 1 — Q9BYB4 (reviewed: Q9BYB4)

Alternative names: DGCRK3, WD repeat-containing protein 14, WD40 repeat-containing protein deleted in VCFS

All UniProt accessions (2): C9JPQ6, Q9BYB4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a critical regulator of DNA damage response (DDR) signaling via specifically regulating phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Highly expressed in heart, liver, skeletal muscle, kidney, spleen, thymus and pancreas. Detected at low levels in lung, placenta and brain.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BYB4-1	1	yes
Q9BYB4-2	2

RefSeq proteins (1): NP_443730* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF00400

UniProt features (14 total): repeat 7, sequence variant 4, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYB4-F1	92.22	0.80

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 84 (showing top): GOBP_BEHAVIOR, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, WANG_RESPONSE_TO_BEXAROTENE_UP, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTRASPECIES_INTERACTION_BETWEEN_ORGANISMS, GRE_C, GOBP_DNA_DAMAGE_RESPONSE, GATA1_03, SANSOM_APC_TARGETS_UP, TGGNNNNNNKCCAR_UNKNOWN, RYTTCCTG_ETS2_B, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE, GOBP_CELL_CYCLE_CHECKPOINT_SIGNALING

GO Biological Process (3): DNA damage checkpoint signaling (GO:0000077), DNA damage response (GO:0006974), social behavior (GO:0035176)

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

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
cellular response to stress	1
behavior	1
biological process involved in intraspecies interaction between organisms	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNB1L	SEPTIN5	Q99719	891
GNB1L	TBX1	O43435	887
GNB1L	DGCR8	Q8WYQ5	883
GNB1L	GP1BB	P13224	870
GNB1L	PRODH	O43272	807
GNB1L	GSC2	O15499	803
GNB1L	PRODH	O43272	792
GNB1L	RANBP1	P43487	786
GNB1L	COMT	P21964	743
GNB1L	CRKL	P46109	724
GNB1L	DGCR2	P98153	714
GNB1L	DGCR6L	Q9BY27	684
GNB1L	DGCR6	Q14129	647
GNB1L	TXNRD2	Q9NNW7	638
GNB1L	ZDHHC8	Q9ULC8	619

IntAct

50 interactions, top by confidence:

A	B	Type	Score
RABGGTB	PIPSL	psi-mi:“MI:0914”(association)	0.530
GNB1L	CCT3	psi-mi:“MI:0914”(association)	0.530
GSTM3	ECT2L	psi-mi:“MI:0914”(association)	0.530
ASPRV1	WDR45B	psi-mi:“MI:0914”(association)	0.530
GNB1L	HSPA2	psi-mi:“MI:0915”(physical association)	0.400
TMEM132A	WWP2	psi-mi:“MI:0914”(association)	0.350
Sidt2	PRSS1	psi-mi:“MI:0914”(association)	0.350
Mis12	CTNNB1	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
GATD1		psi-mi:“MI:0914”(association)	0.350
KCNJ5	ERI3	psi-mi:“MI:0914”(association)	0.350
CNPY2	COL2A1	psi-mi:“MI:0914”(association)	0.350
GAS2L1	GSN	psi-mi:“MI:0914”(association)	0.350
TEKT2	GFAP	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
PAGE1	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CD6	CIBAR1	psi-mi:“MI:0914”(association)	0.350
C19orf25	NBAS	psi-mi:“MI:0914”(association)	0.350
GATD1	MYO9A	psi-mi:“MI:0914”(association)	0.350
PLEKHJ1	AP3B1	psi-mi:“MI:0914”(association)	0.350
RNF7	SOCS2	psi-mi:“MI:0914”(association)	0.350
EVA1B	C2CD2L	psi-mi:“MI:0914”(association)	0.350
RNF181	CHEK1	psi-mi:“MI:0914”(association)	0.350
EIF1AD	CHEK1	psi-mi:“MI:0914”(association)	0.350
POLE3	ERI3	psi-mi:“MI:0914”(association)	0.350

BioGRID (77): GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS), GNB1L (Affinity Capture-MS)

ESM2 similar proteins: A2AKB9, A2RRH5, A2RUS2, O43379, O60336, P58742, Q08BB3, Q0VBY8, Q148I1, Q15334, Q3MHH0, Q3SZD4, Q3U3T8, Q499N3, Q4R3J7, Q4VBE8, Q5FW06, Q5QP82, Q5RCX2, Q5T6F0, Q5U4D9, Q5U4F6, Q5VW00, Q5ZJL7, Q63ZP7, Q6AX81, Q6AY87, Q6NS57, Q6NWH1, Q6P1M3, Q6P809, Q7Z5U6, Q80Y17, Q86W42, Q8AVS9, Q8BGW4, Q8BGZ3, Q8C5V5, Q8HXL3, Q8K4K5

Diamond homologs: A2RA56, A3LXM4, A4RJA0, A7ESR0, A7UWE6, B6HHJ8, B8NG55, C9STX5, F1DLK1, Q9BYB4, Q9EQ15, A0A223GEB2, A1L271, A6H603, G4MQX3, O14775, P23232, P25387, P62881, P62882, Q01369, Q04725, Q10051, Q149M9, Q5GIS3, Q5RDY7, Q61FW2, Q6NUD0, Q6PBY0, Q6PNB6, Q80ZD0, Q9WVB2, A5DR04, B9WJ47, C4YSJ2, Q5ABV4, Q6BPL7, A4IIX9, D9N129, O74184

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	71
Likely benign	13
Benign	13

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2663892	GRCh38/hg38 22q11.21(chr22:18856290-21070117)x3	Pathogenic

SpliceAI

2288 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19801997:TGACC:T	donor_loss	1.0000
22:19801998:GA:G	donor_loss	1.0000
22:19802000:C:CT	donor_loss	1.0000
22:19802215:GCCTG:G	acceptor_loss	1.0000
22:19802216:CCTGC:C	acceptor_loss	1.0000
22:19802217:C:CC	acceptor_gain	1.0000
22:19802218:T:C	acceptor_loss	1.0000
22:19821226:AC:A	donor_gain	1.0000
22:19821227:CC:C	donor_gain	1.0000
22:19788956:CGCAC:C	acceptor_gain	0.9900
22:19788958:CAC:C	acceptor_gain	0.9900
22:19788961:C:G	acceptor_loss	0.9900
22:19788962:T:C	acceptor_loss	0.9900
22:19802212:TCGGC:T	acceptor_gain	0.9900
22:19802213:CGGC:C	acceptor_gain	0.9900
22:19802213:CGGCC:C	acceptor_gain	0.9900
22:19802214:GGC:G	acceptor_gain	0.9900
22:19802215:GC:G	acceptor_gain	0.9900
22:19802216:CC:C	acceptor_gain	0.9900
22:19806758:C:CC	acceptor_gain	0.9900
22:19806759:T:G	acceptor_loss	0.9900
22:19806763:A:T	acceptor_gain	0.9900
22:19820722:ACCT:A	acceptor_loss	0.9900
22:19820723:CCTGT:C	acceptor_loss	0.9900
22:19820724:C:CA	acceptor_loss	0.9900
22:19820724:C:CC	acceptor_gain	0.9900
22:19830050:T:TA	donor_gain	0.9900
22:19851732:T:TA	donor_gain	0.9900
22:19854439:CCA:C	donor_loss	0.9900
22:19854440:CA:C	donor_loss	0.9900

AlphaMissense

2102 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19812447:A:C	S85R	0.989
22:19812447:A:T	S85R	0.989
22:19820599:T:G	S85R	0.989
22:19788764:G:T	A310D	0.983
22:19812419:A:G	W95R	0.978
22:19812419:A:T	W95R	0.978
22:19788732:A:G	W321R	0.977
22:19788732:A:T	W321R	0.977
22:19788887:G:T	A269D	0.977
22:19812357:G:C	F115L	0.977
22:19812357:G:T	F115L	0.977
22:19812359:A:G	F115L	0.977
22:19812417:C:A	W95C	0.977
22:19812417:C:G	W95C	0.977
22:19788736:G:C	S319R	0.976
22:19788736:G:T	S319R	0.976
22:19788738:T:G	S319R	0.976
22:19820698:A:G	W52R	0.970
22:19820698:A:T	W52R	0.970
22:19802030:A:G	W235R	0.969
22:19802030:A:T	W235R	0.969
22:19788740:A:G	I318T	0.968
22:19788750:C:G	D315H	0.966
22:19788758:C:T	G312D	0.965
22:19788784:G:C	F303L	0.964
22:19788784:G:T	F303L	0.964
22:19788786:A:G	F303L	0.964
22:19788860:C:G	R278P	0.963
22:19788762:C:G	A311P	0.962
22:19788881:G:T	A271E	0.961

dbSNP variants (sampled 300 via entrez): RS1000004808 (22:19789743 G>T), RS1000054201 (22:19831145 G>A), RS1000127248 (22:19832693 G>A), RS1000141169 (22:19794413 G>T), RS1000176798 (22:19837341 C>T), RS1000184912 (22:19823840 C>T), RS1000225264 (22:19800246 G>A), RS1000288727 (22:19788870 G>A), RS1000303226 (22:19805105 C>T), RS1000327744 (22:19784440 G>A), RS1000333725 (22:19805384 G>C), RS1000337967 (22:19843156 G>A), RS1000368319 (22:19855966 T>C), RS1000369570 (22:19788476 G>A), RS1000384144 (22:19850952 A>G)

Disease associations

OMIM: gene MIM:610778 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003050_26	Schizophrenia	1.000000e-07
GCST006412_130	Intraocular pressure	5.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724690 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	5
sodium arsenite	affects expression, decreases expression	2
Cisplatin	affects cotreatment, decreases expression	2
Aflatoxin B1	increases methylation	2
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	decreases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Phenobarbital	affects expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Okadaic Acid	increases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697383	Binding	Inhibition of GNB1L (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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