NEUROD6

Summary

NEUROD6 (neuronal differentiation 6, HGNC:13804) is a protein-coding gene on chromosome 7p14.3, encoding Neurogenic differentiation factor 6 (Q96NK8). Activates E box-dependent transcription in collaboration with TCF3/E47.

This gene is a member of the NEUROD family of basic helix-loop-helix transcription factors. The encoded protein may be involved in the development and differentiation of the nervous system.

Source: NCBI Gene 63974 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 29 total — 1 pathogenic
• Transcription factor: yes — 11 downstream targets (CollecTRI)
• MANE Select transcript: NM_022728

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13804
Approved symbol	NEUROD6
Name	neuronal differentiation 6
Location	7p14.3
Locus type	gene with protein product
Status	Approved
Aliases	Atoh2, NEX1M, Math-2, bHLHa2, Nex1
Ensembl gene	ENSG00000164600
Ensembl biotype	protein_coding
OMIM	611513
Entrez	63974

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000297142

RefSeq mRNA: 1 — MANE Select: NM_022728 NM_022728

CCDS: CCDS5434

Canonical transcript exons

ENST00000297142 — 2 exons

Exon	Start	End
ENSE00001085769	31337465	31339289
ENSE00001085770	31340593	31340726

Expression profiles

Bgee: expression breadth broad, 57 present calls, max score 99.73.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.8872 / max 2124.3349, expressed in 94 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83463	4.2713	87
83464	0.2252	52
204404	0.1555	31
83466	0.1415	45
83465	0.0936	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.73	gold quality
ganglionic eminence	UBERON:0004023	99.44	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.24	gold quality
orbitofrontal cortex	UBERON:0004167	94.22	gold quality
CA1 field of hippocampus	UBERON:0003881	93.08	gold quality
prefrontal cortex	UBERON:0000451	89.79	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.77	gold quality
Ammon’s horn	UBERON:0001954	88.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.63	gold quality
cerebral cortex	UBERON:0000956	88.48	gold quality
frontal cortex	UBERON:0001870	88.45	gold quality
frontal lobe	UBERON:0016525	88.45	gold quality
superior frontal gyrus	UBERON:0002661	88.26	gold quality
anterior cingulate cortex	UBERON:0009835	88.11	gold quality
cingulate cortex	UBERON:0003027	88.06	gold quality
neocortex	UBERON:0001950	88.05	gold quality
right frontal lobe	UBERON:0002810	87.00	gold quality
entorhinal cortex	UBERON:0002728	86.72	gold quality
postcentral gyrus	UBERON:0002581	86.66	gold quality
ventricular zone	UBERON:0003053	83.44	gold quality
parietal lobe	UBERON:0001872	83.36	gold quality
embryo	UBERON:0000922	80.33	gold quality
temporal lobe	UBERON:0001871	80.10	gold quality
middle temporal gyrus	UBERON:0002771	79.10	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.18	gold quality
amygdala	UBERON:0001876	77.38	gold quality
primary visual cortex	UBERON:0002436	75.16	gold quality
endothelial cell	CL:0000115	74.93	gold quality
cerebellar vermis	UBERON:0004720	74.81	silver quality
diaphragm	UBERON:0001103	74.14	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10485	yes	3812.51
E-HCAD-5	yes	2654.39
E-MTAB-8894	yes	1777.18
E-GEOD-75140	yes	1714.67
E-ANND-3	no	1.97

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

11 targets.

Target	Regulation
CDKN1A	Activation
GAL	Unknown
GAP43	Activation
KIF5B	Unknown
ME1	Activation
NEUROD1
NGF
PCSK6
PDYN	Unknown
SRGN
YBX1

Upstream regulators (CollecTRI, top): CEBPB, CEBPG

miRNA regulators (miRDB)

97 targeting NEUROD6, 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-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504

Literature-anchored findings (GeneRIF, showing 3)

• cloning and some features of a novel human gene, MATH2, which encodes a protein of 337 amino acid residues with a basic helix loop helix domain and exhibits 98% similarity to mouse Math2 (PMID:12357074)
• NeuroD6 serves as a possible biomarker for Alzheimer disease brains. (PMID:25548427)
• single nucleotide polymorphisms in either the region of NEUROD6 or SNAP25 were significantly associated with Alzheimer’s Disease, in APOE4+ females and APOE4+ males, respectively. (PMID:26395074)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurod6b	ENSDARG00000020794
danio_rerio	neurod6a	ENSDARG00000040008
mus_musculus	Neurod6	ENSMUSG00000037984
rattus_norvegicus	Neurod6	ENSRNOG00000026055
drosophila_melanogaster	amos	FBGN0003270
drosophila_melanogaster	ato	FBGN0010433
drosophila_melanogaster	tap	FBGN0015550
caenorhabditis_elegans		WBGENE00003018
caenorhabditis_elegans		WBGENE00003595

Paralogs (15): NEUROG3 (ENSG00000122859), NEUROD4 (ENSG00000123307), BHLHE23 (ENSG00000125533), NEUROD1 (ENSG00000162992), 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 6 — Q96NK8 (reviewed: Q96NK8)

Alternative names: Class A basic helix-loop-helix protein 2, Protein atonal homolog 2

All UniProt accessions (2): A0A090N7T3, Q96NK8

UniProt curated annotations — full annotation on UniProt →

Function. Activates E box-dependent transcription in collaboration with TCF3/E47. May be a trans-acting factor involved in the development and maintenance of the mammalian nervous system. Transactivates the promoter of its own gene.

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

Subcellular location. Nucleus.

RefSeq proteins (1): NP_073565* (*=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 (5 total): chain 1, domain 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NK8-F1	62.31	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 166 (showing top): ATF_B, RNGTGGGC_UNKNOWN, GOBP_DENTATE_GYRUS_DEVELOPMENT, GCANCTGNY_MYOD_Q6, GOBP_NEUROGENESIS, CREBP1_Q2, TAL1ALPHAE47_01, LHX3_01, CTATGCA_MIR153, GTACAGG_MIR486, GOBP_FOREBRAIN_DEVELOPMENT, MODULE_313, NKX61_01, CREB_Q4, EVI1_05

GO Biological Process (7): sensory organ development (GO:0007423), dentate gyrus development (GO:0021542), positive regulation of transcription by RNA polymerase II (GO:0045944), axon development (GO:0061564), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), cell differentiation (GO:0030154)

GO Molecular Function (7): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA binding (GO:0003677), 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
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
animal organ development	1
hippocampus development	1
anatomical structure development	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
neuron projection development	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
system development	1
cellular developmental process	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
protein binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
nucleic acid 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

2144 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEUROD6	TBR1	Q16650	773
NEUROD6	EMX1	Q04741	714
NEUROD6	FEZF2	Q8TBJ5	713
NEUROD6	SATB2	Q9UPW6	712
NEUROD6	FOXG1	P55315	672
NEUROD6	ASCL1	P50553	496
NEUROD6	EOMES	O95936	489
NEUROD6	POU3F1	Q03052	475
NEUROD6	PAX6	P26367	467
NEUROD6	DLX1	P56177	467
NEUROD6	SNCA	P37840	464
NEUROD6	CDKN1C	P49918	461
NEUROD6	BCL11B	Q9C0K0	461
NEUROD6	GLS	O94925	449
NEUROD6	BDNF	P23560	442
NEUROD6	GAD1	Q99259	442

IntAct

7 interactions, top by confidence:

A	B	Type	Score
NEUROD6	KTN1	psi-mi:“MI:0915”(physical association)	0.400
NEUROD6	RANGAP1	psi-mi:“MI:0915”(physical association)	0.400
	NEUROD6	psi-mi:“MI:0915”(physical association)	0.370
TNIK	NEUROD6	psi-mi:“MI:0915”(physical association)	0.000
DISC1	NEUROD6	psi-mi:“MI:0915”(physical association)	0.000
DSCR9	NEUROD6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): NEUROD6 (Affinity Capture-Western), NEUROD6 (Proximity Label-MS), NEUROD6 (Proximity Label-MS), NEUROD6 (Two-hybrid)

ESM2 similar proteins: A0A140LFM6, B0FZN7, B0FZN8, B0FZN9, B0FZP0, B0FZP1, B0FZP2, B0FZP3, B0S6S9, O08750, O60381, P01105, P10157, P18755, P19102, P32314, Q08D88, Q08DI0, Q16649, Q1LXZ9, Q2KJ34, Q3UPW2, Q3YC04, Q4JM28, Q4R5G6, Q4V7E1, Q5DTV4, Q5FW38, Q5HYM0, Q5R7I3, Q5ZJK5, Q62661, Q66J36, Q66J77, Q68EL6, Q6NRK3, Q6NYU3, Q8AYI2, Q8C8Y5, Q8K402

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	28
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
563420	GRCh37/hg19 7p14.3-13(chr7:30463886-43470805)x3	Pathogenic

SpliceAI

147 predictions. Top by Δscore:

Variant	Effect	Δscore
7:31339287:TACC:T	acceptor_loss	0.8900
7:31339288:ACCT:A	acceptor_loss	0.8900
7:31339290:CTGAA:C	acceptor_loss	0.8900
7:31339291:T:A	acceptor_loss	0.8900
7:31339169:GCTTC:G	acceptor_gain	0.8700
7:31339292:G:C	acceptor_loss	0.8600
7:31339286:TTAC:T	acceptor_gain	0.8500
7:31339293:AAAAA:A	acceptor_loss	0.8300
7:31339294:AAAAA:A	acceptor_loss	0.8300
7:31339244:ACTC:A	acceptor_gain	0.8100
7:31339243:GACTC:G	acceptor_gain	0.8000
7:31339245:CTCAT:C	acceptor_gain	0.8000
7:31339233:C:A	acceptor_gain	0.7800
7:31339242:AGACT:A	acceptor_gain	0.7800
7:31339246:T:A	acceptor_gain	0.7800
7:31340587:TATTA:T	donor_loss	0.7600
7:31340588:ATTAC:A	donor_loss	0.7600
7:31340589:TTACC:T	donor_loss	0.7600
7:31340590:TA:T	donor_loss	0.7600
7:31340591:ACC:A	donor_loss	0.7600
7:31340592:C:T	donor_loss	0.7600
7:31340593:C:A	donor_loss	0.7500
7:31340638:T:TA	donor_gain	0.7500
7:31339162:C:A	acceptor_gain	0.7400
7:31339168:GGCTT:G	acceptor_gain	0.7400
7:31339235:T:TC	acceptor_gain	0.7400
7:31340043:T:C	donor_gain	0.7400
7:31340586:ATATT:A	donor_loss	0.7300
7:31340082:CTG:C	donor_gain	0.7200
7:31339235:T:A	acceptor_gain	0.7000

AlphaMissense

2236 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:31338742:A:C	L176W	1.000
7:31338742:A:G	L176S	1.000
7:31338744:G:C	N175K	1.000
7:31338744:G:T	N175K	1.000
7:31338751:G:A	T173I	1.000
7:31338760:G:A	S170F	1.000
7:31338760:G:T	S170Y	1.000
7:31338763:A:G	L169P	1.000
7:31338763:A:T	L169H	1.000
7:31338771:G:C	C166W	1.000
7:31338772:C:T	C166Y	1.000
7:31338775:A:G	L165S	1.000
7:31338784:A:T	V162D	1.000
7:31338820:A:G	L150P	1.000
7:31338830:A:G	S147P	1.000
7:31338832:A:G	L146P	1.000
7:31338832:A:T	L146H	1.000
7:31338841:A:T	I143N	1.000
7:31338845:A:G	Y142H	1.000
7:31338846:G:C	N141K	1.000
7:31338846:G:T	N141K	1.000
7:31338853:G:T	A139D	1.000
7:31338854:C:G	A139P	1.000
7:31338856:A:G	L138P	1.000
7:31338856:A:T	L138Q	1.000
7:31338859:C:G	R137P	1.000
7:31338861:T:A	L136F	1.000
7:31338861:T:G	L136F	1.000
7:31338862:A:G	L136S	1.000
7:31338868:T:A	E134V	1.000

dbSNP variants (sampled 300 via entrez): RS1001840393 (7:31339171 T>C), RS1001905328 (7:31338615 A>G,T), RS1001908402 (7:31338187 A>G,T), RS1001962404 (7:31338682 G>T), RS1002748450 (7:31342246 A>G), RS1003645866 (7:31342572 G>C), RS1003857835 (7:31342116 G>A), RS1003889071 (7:31341825 T>C), RS1005093330 (7:31340913 A>C), RS1005733216 (7:31337493 T>A), RS1005764195 (7:31337137 T>G), RS1006066665 (7:31339787 T>A), RS1006185216 (7:31340708 T>A), RS1007761943 (7:31339945 G>A), RS1008038320 (7:31339714 A>C,G)

Disease associations

OMIM: gene MIM:611513 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002688_2	Very long-chain saturated fatty acid levels (fatty acid 22:0)	5.000000e-06
GCST006137_13	Serum folate levels	2.000000e-07
GCST90000047_136	Age at first sexual intercourse	3.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006796	very long-chain saturated fatty acid measurement
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cyclosporine	increases methylation	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4K9	SEES3-1V human NEUROD6, clone1	Embryonic stem cell	Male
CVCL_A4L0	SEES3-1V human NEUROD6, clone2	Embryonic stem cell	Male
CVCL_A4L1	SEES3-1V human NEUROD6, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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