BHLHE23

Summary

BHLHE23 (basic helix-loop-helix family member e23, HGNC:16093) is a protein-coding gene on chromosome 20q13.33, encoding Class E basic helix-loop-helix protein 23 (Q8NDY6). May function as transcriptional repressor.

This gene encodes a member of the basic helix-loop-helix transcription factor family. Members of this family contain two highly conserved and functionally distinct domains: the basic domain targets sequence-specific DNA binding, while the helix-loop-helix domain facilitates protein interaction. Studies of a related gene in mouse suggest that the encoded protein may function as a transcriptional repressor in the pancreas and brain, and that it is required for normal retinal function.

Source: NCBI Gene 128408 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 18 total — 1 pathogenic
• MANE Select transcript: NM_080606

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16093
Approved symbol	BHLHE23
Name	basic helix-loop-helix family member e23
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	bA305P22.3, Beta4
Ensembl gene	ENSG00000125533
Ensembl biotype	protein_coding
OMIM	609331
Entrez	128408

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000370346, ENST00000612929

RefSeq mRNA: 1 — MANE Select: NM_080606 NM_080606

CCDS: CCDS33507

Canonical transcript exons

ENST00000612929 — 1 exons

Exon	Start	End
ENSE00003712029	63005927	63006964

Expression profiles

Bgee: expression breadth tissue_specific, 7 present calls, max score 62.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0207 / max 5.1044, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188315	0.0207	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	62.49	gold quality
colonic epithelium	UBERON:0000397	41.40	gold quality
ventricular zone	UBERON:0003053	41.04	gold quality
cortical plate	UBERON:0005343	40.56	silver quality
bone marrow cell	CL:0002092	36.16	gold quality
right atrium auricular region	UBERON:0006631	35.16	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
muscle tissue	UBERON:0002385	31.06	gold quality
sural nerve	UBERON:0015488	30.93	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
urinary bladder	UBERON:0001255	29.45	gold quality
monocyte	CL:0000576	28.94	gold quality
leukocyte	CL:0000738	28.82	gold quality
liver	UBERON:0002107	28.27	gold quality
duodenum	UBERON:0002114	28.14	gold quality
lymph node	UBERON:0000029	27.57	gold quality
right coronary artery	UBERON:0001625	27.26	gold quality
superior frontal gyrus	UBERON:0002661	27.07	gold quality
tonsil	UBERON:0002372	27.05	gold quality
islet of Langerhans	UBERON:0000006	26.55	gold quality
heart	UBERON:0000948	26.50	silver quality
blood	UBERON:0000178	26.43	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	25.89	gold quality
placenta	UBERON:0001987	25.81	gold quality
muscle of leg	UBERON:0001383	24.74	gold quality
primary visual cortex	UBERON:0002436	24.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.25

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
INS
ITGB4
TBXT
TUBB3

JASPAR motifs

Motif	Name	Family
MA0817.1	BHLHE23	Tal-related
MA0817.2	BHLHE23	Tal-related

JASPAR matrix evidence (PMIDs): PMID:9144210

Upstream regulators (CollecTRI, top): ISL1, TFAP2A, TFAP2D

Literature-anchored findings (GeneRIF, showing 2)

• Mouse Bhlhe23 can function as a transcriptional repressor. (PMID:11863370)
• Knockout mouse retinal dysfunction resembles human congenital stationary night blindness. (PMID:15363390)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	bhlhe23	ENSDARG00000037588
mus_musculus	Bhlhe23	ENSMUSG00000045493
rattus_norvegicus	Bhlhe23	ENSRNOG00000010312
drosophila_melanogaster	amos	FBGN0003270
drosophila_melanogaster	ato	FBGN0010433
drosophila_melanogaster	tap	FBGN0015550
caenorhabditis_elegans		WBGENE00003018
caenorhabditis_elegans		WBGENE00003595

Paralogs (15): NEUROG3 (ENSG00000122859), NEUROD4 (ENSG00000123307), NEUROD1 (ENSG00000162992), NEUROD6 (ENSG00000164600), ATOH8 (ENSG00000168874), NEUROD2 (ENSG00000171532), ATOH1 (ENSG00000172238), OLIG3 (ENSG00000177468), NEUROG2 (ENSG00000178403), ATOH7 (ENSG00000179774), BHLHA15 (ENSG00000180535), BHLHE22 (ENSG00000180828), NEUROG1 (ENSG00000181965), OLIG1 (ENSG00000184221), OLIG2 (ENSG00000205927)

Protein

Protein identifiers

Class E basic helix-loop-helix protein 23 — Q8NDY6 (reviewed: Q8NDY6)

Alternative names: Class B basic helix-loop-helix protein 4

All UniProt accessions (2): Q8NDY6, A0A087WXG3

UniProt curated annotations — full annotation on UniProt →

Function. May function as transcriptional repressor. May modulate the expression of genes required for the differentiation and/or maintenance of pancreatic and neuronal cell types. May be important for rod bipolar cell maturation.

Subcellular location. Nucleus.

RefSeq proteins (1): NP_542173* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050359	bHLH_transcription_factors	Family

Pfam: PF00010

UniProt features (3 total): chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NDY6-F1	67.50	0.30

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 38 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_NEUROGENESIS, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_CELL_PROJECTION_ORGANIZATION, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_E_BOX_BINDING, NIKOLSKY_BREAST_CANCER_20Q12_Q13_AMPLICON, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, MEISSNER_NPC_HCP_WITH_H3K27ME3, MEISSNER_BRAIN_HCP_WITH_H3K27ME3, MIKKELSEN_MCV6_HCP_WITH_H3K27ME3, MIKKELSEN_NPC_HCP_WITH_H3K27ME3, MIKKELSEN_MEF_HCP_WITH_H3K27ME3, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOBP_AXON_DEVELOPMENT

GO Biological Process (7): sensory organ development (GO:0007423), positive regulation of transcription by RNA polymerase II (GO:0045944), axon development (GO:0061564), retinal rod cell development (GO:0046548), retinal cell programmed cell death (GO:0046666), negative regulation of retinal cell programmed cell death (GO:0046671), post-embryonic eye morphogenesis (GO:0048050)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	2
eye morphogenesis	2
animal organ development	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
neuron projection development	1
eye photoreceptor cell development	1
retinal rod cell differentiation	1
programmed cell death involved in cell development	1
negative regulation of programmed cell death	1
retinal cell programmed cell death	1
regulation of retinal cell programmed cell death	1
negative regulation of developmental process	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
protein binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BHLHE23	AP3S2	P59780	700
BHLHE23	AP3S1	Q92572	682
BHLHE23	VSX1	Q9NZR4	651
BHLHE23	TCF3	P15883	649
BHLHE23	AP4M1	O00189	573
BHLHE23	KCNMB2	Q9Y691	571
BHLHE23	KCNMB3	Q9NPA1	570
BHLHE23	VSX2	P58304	546
BHLHE23	ASCL5	Q7RTU5	540
BHLHE23	KCNMA1	Q12791	507
BHLHE23	KCNMB1	P78475	478
BHLHE23	BHLHA9	Q7RTU4	471
BHLHE23	BHLHE22	Q8NFJ8	456
BHLHE23	PRDM8	Q9NQV8	423
BHLHE23	LRRC26	Q2I0M4	407

IntAct

9 interactions, top by confidence:

A	B	Type	Score
BHLHE23	CSNK2A2	psi-mi:“MI:0915”(physical association)	0.620
BHLHE23	CSNK2A2	psi-mi:“MI:0914”(association)	0.620
KRT34	BHLHE23	psi-mi:“MI:0915”(physical association)	0.560
BHLHE23	DUSP14	psi-mi:“MI:0914”(association)	0.350
BHLHE23	SPTBN2	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
BHLHE23	KRT34	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (21): BHLHE23 (Affinity Capture-MS), KRT34 (Two-hybrid), FAM26D (Affinity Capture-MS), DSG4 (Affinity Capture-MS), S100A3 (Affinity Capture-MS), CSNK2A2 (Affinity Capture-MS), CSNK2A1 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), HEPHL1 (Affinity Capture-MS), LUC7L (Affinity Capture-MS), C1QBP (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), DUSP14 (Affinity Capture-MS), CSNK2B (Affinity Capture-MS), SEMG2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I6AGW3, A2A9A2, A6NMB9, A8MYZ6, E9PZZ1, J3QK54, O02755, O02756, O35392, O35767, O60548, O70220, P05554, P17676, P21272, P28033, P35713, P42582, P49715, P49716, P52952, P53566, P58012, Q12952, Q13461, Q14526, Q60843, Q61345, Q63244, Q63250, Q6BEB4, Q6VFT5, Q6VFT6, Q6ZQN5, Q70KY4, Q8IU81, Q8MIP2, Q8NDY6, Q8R2I0, Q98937

Diamond homologs: A8E5T6, B6VQA1, O09029, O09105, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O45489, O57598, O88940, O96004, O96642, P10627, P13903, P46581, P48985, P48986, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70447, P70562, P70595, P70660, P70661, P79765, P79766, P79782, P79920, P97832, Q08DI0, Q0V9X5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	16
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
816132	GRCh37/hg19 20q13.32-13.33(chr20:56788101-62762405)x3	Pathogenic

SpliceAI

140 predictions. Top by Δscore:

Variant	Effect	Δscore
20:63006469:C:CA	donor_gain	0.7500
20:63006963:C:CT	donor_gain	0.6300
20:63006964:T:TT	donor_gain	0.6300
20:63006969:C:A	donor_gain	0.6300
20:63006985:T:TA	donor_gain	0.5600
20:63006962:TC:T	donor_gain	0.5400
20:63006968:T:TA	donor_gain	0.5300
20:63006864:G:A	donor_gain	0.5000
20:63006683:AGTG:A	donor_gain	0.4800
20:63006138:C:CC	acceptor_gain	0.4400
20:63006328:CGGG:C	donor_gain	0.4400
20:63006155:A:AT	acceptor_gain	0.4100
20:63006365:T:TA	donor_gain	0.4100
20:63006160:G:GA	acceptor_gain	0.4000
20:63006509:T:TA	donor_gain	0.4000
20:63006108:A:AC	donor_gain	0.3800
20:63006109:C:CC	donor_gain	0.3800
20:63006215:C:CA	donor_gain	0.3700
20:63006246:T:C	donor_gain	0.3700
20:63006268:C:CA	acceptor_gain	0.3700
20:63006269:A:AA	acceptor_gain	0.3700
20:63006133:GGCGC:G	acceptor_loss	0.3600
20:63006134:GCGCC:G	acceptor_loss	0.3600
20:63006135:CGCC:C	acceptor_loss	0.3600
20:63006136:GCC:G	acceptor_loss	0.3600
20:63006137:CCTG:C	acceptor_loss	0.3600
20:63006138:CTGC:C	acceptor_loss	0.3600
20:63006139:T:A	acceptor_loss	0.3600
20:63006251:T:TA	donor_gain	0.3600
20:63006319:G:A	donor_gain	0.3600

AlphaMissense

1526 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:63006275:A:G	I151T	1.000
20:63006275:A:T	I151N	1.000
20:63006287:G:T	A147D	1.000
20:63006290:A:G	L146P	1.000
20:63006293:A:G	L145P	1.000
20:63006296:A:G	L144P	1.000
20:63006296:A:T	L144Q	1.000
20:63006307:C:A	K140N	1.000
20:63006307:C:G	K140N	1.000
20:63006308:T:A	K140M	1.000
20:63006309:T:C	K140E	1.000
20:63006309:T:G	K140Q	1.000
20:63006311:G:A	S139F	1.000
20:63006359:A:G	L123P	1.000
20:63006376:G:C	N117K	1.000
20:63006376:G:T	N117K	1.000
20:63006380:A:G	L116P	1.000
20:63006380:A:T	L116Q	1.000
20:63006388:C:A	M113I	1.000
20:63006388:C:G	M113I	1.000
20:63006388:C:T	M113I	1.000
20:63006400:C:A	E109D	1.000
20:63006400:C:G	E109D	1.000
20:63006275:A:C	I151S	0.999
20:63006288:C:G	A147P	0.999
20:63006296:A:C	L144R	0.999
20:63006299:G:T	T143K	0.999
20:63006305:A:T	I141N	0.999
20:63006311:G:T	S139Y	0.999
20:63006347:A:G	I127T	0.999

dbSNP variants (sampled 300 via entrez): RS1000631529 (20:63008785 C>A,G), RS1000959981 (20:63006670 G>A), RS1002407737 (20:63005964 C>T), RS1003430693 (20:63008719 T>G), RS1004178747 (20:63005556 T>C), RS1004407753 (20:63007968 G>A), RS1004522429 (20:63005775 C>A,G), RS1007535583 (20:63007870 G>A), RS1007614923 (20:63007912 C>G), RS1007876441 (20:63008026 G>T), RS1008065928 (20:63007590 C>T), RS1008284633 (20:63006736 G>T), RS1010811700 (20:63007826 T>C), RS1011987816 (20:63007237 G>A), RS1012065715 (20:63007017 C>T)

Disease associations

OMIM: gene MIM:609331 | 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
GCST007726_3	Anti-Toxoplasma gondii IgG seropositivity	8.000000e-07
GCST010002_71	Refractive error	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007047	Toxoplasma gondii seropositivity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	1
ferrous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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