NEUROD4

Summary

NEUROD4 (neuronal differentiation 4, HGNC:13802) is a protein-coding gene on chromosome 12q13.2, encoding Neurogenic differentiation factor 4 (Q9HD90). Probably acts as a transcriptional activator.

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and E-box binding activity. Predicted to be involved in neuron differentiation; positive regulation of cell differentiation; and positive regulation of transcription by RNA polymerase II. Predicted to act upstream of or within Notch signaling pathway; cell fate commitment; and neurogenesis. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 58158 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_021191

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13802
Approved symbol	NEUROD4
Name	neuronal differentiation 4
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	Atoh3, ATH-3, MATH-3, bHLHa4
Ensembl gene	ENSG00000123307
Ensembl biotype	protein_coding
OMIM	611635
Entrez	58158

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000242994

RefSeq mRNA: 1 — MANE Select: NM_021191 NM_021191

CCDS: CCDS8886

Canonical transcript exons

ENST00000242994 — 2 exons

Exon	Start	End
ENSE00000838468	55026431	55030017
ENSE00001117345	55019974	55020313

Expression profiles

Bgee: expression breadth broad, 29 present calls, max score 92.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.8958 / max 2532.3005, expressed in 120 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125949	3.2053	110
125947	0.3464	50
125948	0.3441	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	92.37	gold quality
ventricular zone	UBERON:0003053	79.33	gold quality
embryo	UBERON:0000922	75.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.58	silver quality
pituitary gland	UBERON:0000007	73.16	gold quality
adenohypophysis	UBERON:0002196	72.62	gold quality
lateral globus pallidus	UBERON:0002476	61.66	gold quality
tibialis anterior	UBERON:0001385	60.51	silver quality
pancreatic ductal cell	CL:0002079	60.29	silver quality
ileal mucosa	UBERON:0000331	60.16	silver quality
cortical plate	UBERON:0005343	57.65	gold quality
nasal cavity epithelium	UBERON:0005384	56.06	gold quality
endothelial cell	CL:0000115	52.44	gold quality
deltoid	UBERON:0001476	51.94	gold quality
left ventricle myocardium	UBERON:0006566	51.64	gold quality
epithelial cell of pancreas	CL:0000083	51.25	gold quality
parotid gland	UBERON:0001831	50.00	gold quality
quadriceps femoris	UBERON:0001377	49.98	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.52	gold quality
substantia nigra pars reticulata	UBERON:0001966	49.22	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
myocardium	UBERON:0002349	49.19	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
cerebellar vermis	UBERON:0004720	48.93	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
vastus lateralis	UBERON:0001379	48.47	gold quality
upper leg skin	UBERON:0004262	48.27	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	881.05
E-MTAB-7316	yes	45.66
E-GEOD-137537	yes	18.92
E-ANND-3	yes	2.62

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
FGFR1
KRT9
ME3
VIPR1

Upstream regulators (CollecTRI, top): CHD8, FOXN4, ISL1, NEUROG2, NEUROG3, NFIA, NFIB, NFIX, RELA

miRNA regulators (miRDB)

132 targeting NEUROD4, 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-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1271-5P	99.91	71.99	1972

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurod4	ENSDARG00000003469
mus_musculus	Neurod4	ENSMUSG00000048015
rattus_norvegicus	Neurod4	ENSRNOG00000008449
drosophila_melanogaster	amos	FBGN0003270
drosophila_melanogaster	ato	FBGN0010433
drosophila_melanogaster	tap	FBGN0015550
caenorhabditis_elegans		WBGENE00003018
caenorhabditis_elegans		WBGENE00003595

Paralogs (15): NEUROG3 (ENSG00000122859), BHLHE23 (ENSG00000125533), 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

Neurogenic differentiation factor 4 — Q9HD90 (reviewed: Q9HD90)

Alternative names: Class A basic helix-loop-helix protein 4, Protein atonal homolog 3

All UniProt accessions (1): Q9HD90

UniProt curated annotations — full annotation on UniProt →

Function. Probably acts as a transcriptional activator. Mediates neuronal differentiation. Required for the regulation of amacrine cell fate specification in the retina.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein.

Subcellular location. Nucleus.

Post-translational modifications. Serine or threonine phosphorylation within the basic region may regulate neurogenic activity.

RefSeq proteins (1): NP_067014* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR016637	TF_bHLH_NeuroD	Family
IPR022575	NeuroD_DUF	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050359	bHLH_transcription_factors	Family

Pfam: PF00010, PF12533

UniProt features (8 total): region of interest 2, compositionally biased region 2, chain 1, domain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HD90-F1	63.06	0.26

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 139 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, MARTINEZ_RB1_TARGETS_UP, TCF4_Q5, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GGARNTKYCCA_UNKNOWN, GOCC_CENTROSOME, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION, GOBP_NEURON_MIGRATION, HFH1_01, AACTTT_UNKNOWN

GO Biological Process (15): Notch signaling pathway (GO:0007219), neuroblast proliferation (GO:0007405), amacrine cell differentiation (GO:0035881), camera-type eye development (GO:0043010), cell fate commitment (GO:0045165), positive regulation of cell differentiation (GO:0045597), positive regulation of transcription by RNA polymerase II (GO:0045944), oligodendrocyte differentiation (GO:0048709), axon development (GO:0061564), motor neuron migration (GO:0097475), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), cell differentiation (GO:0030154), neuron development (GO:0048666), retina development in camera-type eye (GO:0060041)

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), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific double-stranded DNA binding (GO:1990837)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
cellular developmental process	2
regulation of transcription by RNA polymerase II	2
cell surface receptor signaling pathway	1
generation of neurons	1
neural precursor cell proliferation	1
neural retina development	1
central nervous system neuron differentiation	1
eye development	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
central nervous system development	1
glial cell differentiation	1
neuron projection development	1
neuron migration	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
neuron differentiation	1
cell development	1
camera-type eye development	1
anatomical structure development	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
nucleic acid binding	1
binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEUROD4	FOXN4	Q96NZ1	936
NEUROD4	ASCL1	P50553	755
NEUROD4	ISL1	P20663	754
NEUROD4	LHX3	Q9UBR4	679
NEUROD4	HOXB2	P10913	652
NEUROD4	VSX2	P58304	629
NEUROD4	PROX1	Q92786	629
NEUROD4	HOXA2	O43364	600
NEUROD4	PAX6	P26367	593
NEUROD4	POU4F2	Q12837	558
NEUROD4	PHOX2B	Q99453	549
NEUROD4	CRX	O43186	523
NEUROD4	BARHL2	Q9NY43	508
NEUROD4	HES5	Q5TA89	477
NEUROD4	POU4F1	Q01851	457

IntAct

15 interactions, top by confidence:

A	B	Type	Score
PIN1	NEUROD4	psi-mi:“MI:0915”(physical association)	0.560
TCF4	NEUROD4	psi-mi:“MI:0915”(physical association)	0.560
MAGEB4	NEUROD4	psi-mi:“MI:0915”(physical association)	0.560
GABRB1	NEUROD4	psi-mi:“MI:0915”(physical association)	0.370
LRRN2	NEUROD4	psi-mi:“MI:0915”(physical association)	0.370
NEUROD4	POTEF	psi-mi:“MI:0914”(association)	0.350
NEUROD4	TCF4	psi-mi:“MI:0915”(physical association)	0.000
MAGEB4	NEUROD4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): NEUROD4 (Two-hybrid), PIN1 (Two-hybrid), TCF4 (Two-hybrid), NEUROD4 (Positive Genetic), SRP19 (Affinity Capture-MS), ADPRHL2 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), POTEF (Affinity Capture-MS), TCF3 (Affinity Capture-MS), NEUROD4 (Affinity Capture-MS), NEUROD4 (Affinity Capture-MS), NEUROD4 (Affinity Capture-MS), NEUROD4 (Affinity Capture-MS), NEUROD4 (Two-hybrid), NEUROD4 (Two-hybrid)

ESM2 similar proteins: A3KNX5, A5YC49, A6NJ46, A6NNA5, F1Q4R9, O09105, O35137, P12979, P15173, P15375, P17920, P19335, P20428, P23409, P28322, P31276, P34060, P34061, P43268, P43688, P48985, P49812, P70368, P70436, P70661, Q01795, Q08856, Q1KKY2, Q32NH9, Q3MHT3, Q3UHX8, Q3YFL6, Q4G112, Q5ND04, Q5RJB0, Q5TIS6, Q62798, Q66HH3, Q66IG8, Q6VNZ9

Diamond homologs: A6NI15, O08574, O09105, O42202, P41894, P46581, P48986, P79765, P79766, P79920, P97309, Q08DI0, Q0VG99, Q13562, Q28C89, Q4R5G6, Q60430, Q60867, Q64289, Q90ZL1, Q91616, Q96NK8, Q9BRJ9, Q9DEQ9, Q9HD90, Q9JK54, Q9W690, Q9W6C7, Q9Y4Z2, A8E5T6, B6VQA1, O09029, O13125, O13126, O16867, O35437, O42606, O43680, O45489, O57598

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NEUROG3	“down-regulates quantity by repression”	NEUROD4	“transcriptional regulation”
NFIA	“up-regulates quantity”	NEUROD4	“transcriptional regulation”
NFIB	“up-regulates quantity”	NEUROD4	“transcriptional regulation”
NFIX	“up-regulates quantity”	NEUROD4	“transcriptional regulation”
CHD8	“down-regulates quantity”	NEUROD4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

185 predictions. Top by Δscore:

Variant	Effect	Δscore
12:55026429:A:AG	acceptor_gain	0.9900
12:55026430:G:GG	acceptor_gain	0.9900
12:55026430:GA:G	acceptor_gain	0.9900
12:55020309:CCGAG:C	donor_loss	0.9700
12:55020310:CGAG:C	donor_loss	0.9700
12:55020311:GAGGT:G	donor_loss	0.9700
12:55020312:AGGT:A	donor_loss	0.9700
12:55020314:G:GA	donor_loss	0.9700
12:55020315:T:A	donor_loss	0.9700
12:55026425:TTCCA:T	acceptor_loss	0.9700
12:55026427:CCAGA:C	acceptor_loss	0.9700
12:55026429:A:G	acceptor_loss	0.9700
12:55026430:G:A	acceptor_loss	0.9700
12:55026430:GAGT:G	acceptor_gain	0.9700
12:55020311:GAG:G	donor_gain	0.9400
12:55020297:A:T	donor_gain	0.9300
12:55026430:GAGTC:G	acceptor_gain	0.9100
12:55020314:G:GG	donor_gain	0.9000
12:55020123:G:GT	donor_gain	0.8900
12:55020296:G:GT	donor_gain	0.8600
12:55026430:G:C	acceptor_gain	0.8600
12:55020316:GA:G	donor_loss	0.8500
12:55026428:CAG:C	acceptor_gain	0.8300
12:55026429:AGA:A	acceptor_gain	0.8300
12:55026427:CCAG:C	acceptor_gain	0.8200
12:55020239:G:GT	donor_gain	0.7500
12:55026417:T:G	acceptor_loss	0.7200
12:55020124:A:T	donor_gain	0.6100
12:55020176:GAG:G	donor_gain	0.6000
12:55026426:TCCAG:T	acceptor_gain	0.5900

AlphaMissense

2182 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:55026705:G:C	R89T	1.000
12:55026706:A:C	R89S	1.000
12:55026706:A:T	R89S	1.000
12:55026713:G:C	A92P	1.000
12:55026714:C:A	A92D	1.000
12:55026718:T:A	N93K	1.000
12:55026718:T:G	N93K	1.000
12:55026719:G:C	A94P	1.000
12:55026724:A:C	R95S	1.000
12:55026724:A:T	R95S	1.000
12:55026725:G:A	E96K	1.000
12:55026726:A:C	E96A	1.000
12:55026726:A:T	E96V	1.000
12:55026727:A:C	E96D	1.000
12:55026727:A:T	E96D	1.000
12:55026729:G:C	R97P	1.000
12:55026734:C:G	R99G	1.000
12:55026734:C:T	R99W	1.000
12:55026735:G:C	R99P	1.000
12:55026738:T:A	M100K	1.000
12:55026738:T:C	M100T	1.000
12:55026738:T:G	M100R	1.000
12:55026740:C:G	H101D	1.000
12:55026741:A:C	H101P	1.000
12:55026747:T:A	L103Q	1.000
12:55026747:T:C	L103P	1.000
12:55026749:A:G	N104D	1.000
12:55026750:A:T	N104I	1.000
12:55026751:T:A	N104K	1.000
12:55026751:T:G	N104K	1.000

dbSNP variants (sampled 300 via entrez): RS1000437275 (12:55020271 C>G,T), RS1000468533 (12:55019904 T>C), RS1000575079 (12:55026273 T>C), RS1001231042 (12:55020609 C>T), RS1001585366 (12:55019587 C>T), RS1001602221 (12:55020266 T>C), RS1001786091 (12:55026113 T>C), RS1002091790 (12:55025289 G>C), RS1002215516 (12:55025794 A>G), RS1002543183 (12:55029467 G>A), RS1002895840 (12:55030431 A>G), RS1003234813 (12:55018366 A>G), RS1003265888 (12:55018129 T>A,C), RS1003487178 (12:55024386 A>G,T), RS1003863942 (12:55024655 G>C)

Disease associations

OMIM: gene MIM:611635 | 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
GCST002935_8	Lead levels	1.000000e-06
GCST003123_27	Severe influenza A (H1N1) infection	1.000000e-10
GCST007995_38	Asthma (childhood onset)	1.000000e-10
GCST008181_20	Spontaneous preterm birth without premature rupture of membranes	3.000000e-06
GCST010002_217	Refractive error	6.000000e-174

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001488	influenza A (H1N1)
EFO:0006917	spontaneous preterm birth

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
clothianidin	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Lead	affects expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4K6	SEES3-1V human NEUROD4, clone1	Embryonic stem cell	Male
CVCL_A4K7	SEES3-1V human NEUROD4, clone2	Embryonic stem cell	Male
CVCL_A4K8	SEES3-1V human NEUROD4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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