NEUROD1

Summary

NEUROD1 (neuronal differentiation 1, HGNC:7762) is a protein-coding gene on chromosome 2q31.3, encoding Neurogenic differentiation factor 1 (Q13562). Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5’-CANNTG-3'.

This gene encodes a member of the NeuroD family of basic helix-loop-helix (bHLH) transcription factors. The protein forms heterodimers with other bHLH proteins and activates transcription of genes that contain a specific DNA sequence known as the E-box. It regulates expression of the insulin gene, and mutations in this gene result in type II diabetes mellitus.

Source: NCBI Gene 4760 — RefSeq curated summary.

At a glance

• Gene–disease (curated): permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome (Strong, GenCC) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 337 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 33
• Transcription factor: yes — 77 downstream targets (CollecTRI)
• MANE Select transcript: NM_002500

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7762
Approved symbol	NEUROD1
Name	neuronal differentiation 1
Location	2q31.3
Locus type	gene with protein product
Status	Approved
Aliases	BETA2, BHF-1, NeuroD, bHLHa3, MODY6
Ensembl gene	ENSG00000162992
Ensembl biotype	protein_coding
OMIM	601724
Entrez	4760

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000295108, ENST00000496876, ENST00000683166, ENST00000683430, ENST00000684079

RefSeq mRNA: 1 — MANE Select: NM_002500 NM_002500

CCDS: CCDS2283

Canonical transcript exons

ENST00000295108 — 2 exons

Exon	Start	End
ENSE00001070446	181676467	181678871
ENSE00001907026	181680430	181680517

Expression profiles

Bgee: expression breadth ubiquitous, 115 present calls, max score 99.51.

FANTOM5 (CAGE): breadth broad, TPM avg 5.3800 / max 1235.1963, expressed in 188 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32726	4.6741	167
32727	0.2594	56
32728	0.2378	67
32721	0.0767	25
32722	0.0398	16
32720	0.0333	18
32724	0.0223	5
32723	0.0216	14
32725	0.0149	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
paraflocculus	UBERON:0005351	99.51	gold quality
cerebellar vermis	UBERON:0004720	99.46	gold quality
cerebellum	UBERON:0002037	97.99	gold quality
cerebellar cortex	UBERON:0002129	97.90	gold quality
cerebellar hemisphere	UBERON:0002245	97.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.87	gold quality
islet of Langerhans	UBERON:0000006	95.38	gold quality
ganglionic eminence	UBERON:0004023	90.43	gold quality
pons	UBERON:0000988	88.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.73	gold quality
adult organism	UBERON:0007023	84.07	gold quality
cortical plate	UBERON:0005343	82.12	gold quality
type B pancreatic cell	CL:0000169	81.99	silver quality
middle temporal gyrus	UBERON:0002771	80.86	gold quality
pancreas	UBERON:0001264	77.88	gold quality
Brodmann (1909) area 10	UBERON:0013541	76.95	gold quality
frontal pole	UBERON:0002795	76.43	gold quality
primary visual cortex	UBERON:0002436	75.20	gold quality
buccal mucosa cell	CL:0002336	75.04	silver quality
embryo	UBERON:0000922	74.61	gold quality
Ammon’s horn	UBERON:0001954	74.58	gold quality
CA1 field of hippocampus	UBERON:0003881	74.53	silver quality
Brodmann (1909) area 23	UBERON:0013554	73.98	gold quality
endothelial cell	CL:0000115	72.59	silver quality
duodenum	UBERON:0002114	72.29	gold quality
entorhinal cortex	UBERON:0002728	70.70	gold quality
body of pancreas	UBERON:0001150	70.31	gold quality
right frontal lobe	UBERON:0002810	70.12	gold quality
middle frontal gyrus	UBERON:0002702	69.68	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	69.48	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1087.73
E-MTAB-9906	yes	1018.01
E-MTAB-11121	yes	940.36
E-GEOD-125970	yes	803.67
E-MTAB-8894	yes	440.49
E-MTAB-7316	yes	35.85
E-GEOD-83139	yes	9.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

77 targets.

Target	Regulation
ABCC8	Activation
ADAM2
AK1
ATOH1	Unknown
BHLHE40
CD74
CD79A
CDH17
CDKN1A	Repression
COL1A2
CREBBP
DCT
DLD
DLL1	Activation
EPO
FOS	Activation
G6PC2	Activation
GAL	Unknown
GAP43
GCG
GCK
GDNF
GH1
GHRL
GJD2
GK
GNAL	Repression
GNRHR	Activation
HAND2
HES1

JASPAR motifs

Motif	Name	Family
MA1109.1	NEUROD1	Tal-related
MA1109.2	NEUROD1	Tal-related

JASPAR matrix evidence (PMIDs): PMID:9858593

Upstream regulators (CollecTRI, top): ATOH7, ESR1, FOXA2, FOXN4, FOXO1, HES1, INSM1, ISL1, MAFA, NEUROD1, NEUROD2, NEUROD6, NEUROG1, NEUROG2, NEUROG3, NFIA, NFIB, NFIX, NR0B2, PAX6, PDX1, SOX2, SP3, TCF12, ZFHX3, ZNF236

miRNA regulators (miRDB)

194 targeting NEUROD1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783

Literature-anchored findings (GeneRIF, showing 40)

• regulator of insulin transcription (PMID:11755474)
• expression during trophoblast invasion (PMID:11900979)
• Beta-cell dysfunction in late-onset diabetic subjects carrying homozygous mutation in transcription factor NeuroD1. (PMID:12200761)
• The genetic polymorphism in NeuroD is associated with the development of early-onset type 2 diabetes. The presence of Thr45 allele may represent a risk factor for early-onset type 2 diabetes among Chinese. (PMID:12476420)
• Polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children (PMID:12639765)
• Ala5Thr polymorphism of NeuroD1 plays a role in the risk of NIDDM in the examined Polish population (PMID:12861411)
• NeuroD1/E47 transcription factors up-regulate IA-1 gene expression through the proximal E-box element of the IA-1 promoter (PMID:12890672)
• Ala45 variant of BETA2/NeuroD1 may be associated with IDDM in Caucasians. (PMID:12951629)
• NeuroD1 is differentially expressed in pituitary adenomas and its possible ontogenetic and/or pathogenetic implications in non-corticotroph tumors are discussed. (PMID:14759067)
• No evidence of Ala(45)Thr polymorphism of the NeueroD gene and type 1 diabetes. (PMID:15047635)
• Focus of this review is on recent progress in understanding the important role of BETA2/NeuroD1 in initiating neuronal differentiation and maintaining the nervous system. (PMID:15247487)
• Polymorphism contributes to glucose intolerance in a South Indian population. (PMID:15277395)
• NeuroD controls both common and distinct sets of molecules involved in cell survival and differentiation in different tissue types [review] (PMID:15650322)
• co-expression and functional synergism of these beta-cell enriched transactivators, MafA, Pdx1, and Beta2, are critical for establishing the beta-cell-specific and efficient expression of the insulin gene. (PMID:15993959)
• the SREBP-1c.BETA2.E47 complex is in a DNA looping structure which is required for efficient recruitment of CREB-binding protein/p300 (PMID:16055439)
• we demonstrated that ISL1 and BETA2 could activate insulin gene transcription synergistically. (PMID:16321656)
• Gender-specific association of the Ala45Thr variant of NEUROD1 with Type 1 diabetes in Brazilian women. (PMID:16357810)
• results presented in this study define INSM1 as a transcriptional repressor of the neuroD/b2 gene. The molecular mechanism of INSM1 transcriptional repression is attributed to the recruitment of cyclin D1 and HDAC-1 and -3 (PMID:16569215)
• The NeuroD1-Ala45Thr variation may itself have an important role in susceptibility to or be in disequilibrium with early-onset T2DM in Chinese. The Ala45Thr may affect the onset pattern of T2DM, i.e., early-onset but not late-onset T2DM in Chinese. (PMID:16773428)
• helix-loop-helix (HLH) domain of basic helix-loop-helix (bHLH) family proteins such as NeuroD facilitate protein transduction into various cell lines. (PMID:16870135)
• Expression of NeuroD1 versus chromogranin-A is more frequent in pCA, and correlates to increased indicators of malignancy in moderately to poorly differentiated pCA. (PMID:17126478)
• These results suggest that NeuroD plays an important role in regulated exocytosis by inducing expressions of various components required in the process. (PMID:17217914)
• A study evaluating the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes is presented. (PMID:17327436)
• Mutation in the NeuroD1/BETA2 gene contributes to the development of diabetes (PMID:17440689)
• Expression of NeuroD1 versus chromogranin-A is more frequent in pCA, and correlates to increased indicators of malignancy in moderately to poorly differentiated pCA. (PMID:17985422)
• We report a novel disease-associated variant in NEUROD1 identified among a set of MODYX families (PMID:18331410)
• NeuroD has a role in the regulation of pulmonary neuroendocrine and alveolar morphogenesis (PMID:18339630)
• NEUROD1 methylation is a chemosensitivity marker in estrogen receptor-negative breast cancer. (PMID:18519782)
• High NeuroD expression was seen in all well-differentiated gastroenteropancreatic neuroendocrine carcinoma and tumor (carcinoid) patients. (PMID:18587321)
• Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression (PMID:19307926)
• There was no association between methylation and expression in breast tumour specimens, with only 14% exhibiting NEUROD1 expression (PMID:19353266)
• These results suggest that ISL1 is a transcriptional activator for insulin gene expression, and the interactions of ISL1 with BETA2 are required for the transcriptional activity of the insulin gene. (PMID:19619559)
• No significant association of NEUROD1 with retinopathy or nephropathy in Croatian patients with type I diabetes (PMID:20120526)
• syndrome resulting from homozygous loss of function mutations in NEUROD1 which is characterized by permanent neonatal diabetes. (PMID:20573748)
• Human NeuroD1 under control of the cytokeratin 19 promoter can induce differerentiation of pancreatic epithelial cells into insulin producing cells. (PMID:20692411)
• NeuroD alone may not be sufficient to induce regulated insulin release in insulin-producing liver cells. (PMID:21084850)
• ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription. (PMID:21278380)
• Findings establish the critical role of the neuronal differentiation factor NeuroD1 in neuroblastoma as well as its functional relationship with the neuronal repellent factor Slit2. (PMID:21349947)
• Most, if not all, nasal chemosensory neurons derive from NeuroD1-expressing globose basal cells of the immediate neuronal precursor variety. (PMID:21800309)
• The overexpression of NeuroD may contribute to the tumorogenesis and development of pancreatic carcinoma, and is closely correlated to the cancer cell proliferation, p53 signal pathway and neural invasion. (PMID:22455846)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurod1	ENSDARG00000019566
mus_musculus	Neurod1	ENSMUSG00000034701
rattus_norvegicus	Neurod1	ENSRNOG00000005609
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), 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 1 — Q13562 (reviewed: Q13562)

Alternative names: Class A basic helix-loop-helix protein 3

All UniProt accessions (2): A0A0S2Z493, Q13562

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5’-CANNTG-3’. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis.

Subunit / interactions. Efficient DNA-binding requires dimerization with another bHLH protein. Heterodimer with TCF3/E47; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element. Interacts with EP300; the interaction is inhibited by NR0B2. Interacts with RREB1. Interacts with ATOH8.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated. In islet cells, phosphorylated on Ser-274 upon glucose stimulation; which may be required for nuclear localization. In activated neurons, phosphorylated on Ser-335; which promotes dendritic growth. Phosphorylated by MAPK1; phosphorylation regulates heterodimerization and DNA-binding activities. Phosphorylation on Ser-266 and Ser-274 increases transactivation on the insulin promoter in glucose-stimulated insulinoma cells.

Disease relevance. Maturity-onset diabetes of the young 6 (MODY6) [MIM:606394] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Disease susceptibility is associated with variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_002491* (*=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 (20 total): sequence variant 6, modified residue 5, sequence conflict 3, compositionally biased region 2, chain 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13562-F1	62.39	0.24

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 (5): 335, 162, 259, 266, 274

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-210746	Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells
R-HSA-1266738	Developmental Biology
R-HSA-186712	Regulation of beta-cell development

MSigDB gene sets: 426 (showing top): GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_DIGESTION, GOBP_HINDBRAIN_DEVELOPMENT, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GCANCTGNY_MYOD_Q6, GOBP_INSULIN_SECRETION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP

GO Biological Process (38): pancreatic A cell fate commitment (GO:0003326), pancreatic PP cell fate commitment (GO:0003329), transcription by RNA polymerase II (GO:0006366), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), sensory organ development (GO:0007423), response to glucose (GO:0009749), anterior/posterior pattern specification (GO:0009952), dentate gyrus development (GO:0021542), cerebellum development (GO:0021549), neurogenesis (GO:0022008), signal transduction involved in regulation of gene expression (GO:0023019), insulin secretion (GO:0030073), endocrine pancreas development (GO:0031018), positive regulation of insulin secretion (GO:0032024), amacrine cell differentiation (GO:0035881), enteroendocrine cell differentiation (GO:0035883), glucose homeostasis (GO:0042593), positive regulation of apoptotic process (GO:0043065), positive regulation of cell differentiation (GO:0045597), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of receptor signaling pathway via JAK-STAT (GO:0046426), embryonic organ morphogenesis (GO:0048562), inner ear development (GO:0048839), regulation of insulin secretion (GO:0050796), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), regulation of intestinal epithelial structure maintenance (GO:0060730), axon development (GO:0061564), cellular response to glucocorticoid stimulus (GO:0071385), negative regulation of type B pancreatic cell apoptotic process (GO:2000675), regulation of DNA-templated transcription (GO:0006355), nervous system development (GO:0007399), cell differentiation (GO:0030154), hindbrain development (GO:0030902), camera-type eye development (GO:0043010), cell fate commitment (GO:0045165), regulation of neuron differentiation (GO:0045664)

GO Molecular Function (13): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Regulation of beta-cell development	2
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
epithelial cell fate commitment	2
cell differentiation	2
binding	2
pancreatic A cell differentiation	1
pancreatic PP cell differentiation	1
DNA-templated transcription	1
cell surface receptor signaling pathway via STAT	1
animal organ development	1
response to hexose	1
regionalization	1
hippocampus development	1
metencephalon development	1
nervous system development	1
signal transduction	1
regulation of gene expression	1
protein secretion	1
peptide hormone secretion	1
pancreas development	1
endocrine system development	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
neural retina development	1
central nervous system neuron differentiation	1
epithelial cell differentiation	1
carbohydrate homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of cell differentiation	1
positive regulation of cellular process	1
positive regulation of developmental process	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
chromatin	1

Protein interactions and networks

STRING

2818 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEUROD1	PAX4	O43316	940
NEUROD1	INSM1	Q01101	929
NEUROD1	INS	P01308	866
NEUROD1	SLC2A2	P11168	863
NEUROD1	FOXN4	Q96NZ1	859
NEUROD1	HNF1A	P20823	856
NEUROD1	PAX6	P26367	836
NEUROD1	TCF3	P15883	825
NEUROD1	PDX1	P52945	813
NEUROD1	ISL1	P20663	809
NEUROD1	NKX6-1	P78426	797
NEUROD1	MAFA	Q8NHW3	782
NEUROD1	NKX6-2	Q9C056	779
NEUROD1	NKX2-2	O95096	778
NEUROD1	GCG	P01275	771

IntAct

40 interactions, top by confidence:

A	B	Type	Score
NEUROD1	TCF12	psi-mi:“MI:0915”(physical association)	0.670
TCF4	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560
NEUROD1		psi-mi:“MI:0915”(physical association)	0.560
NEUROD1	FKBP1A	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560
NDUFS1	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560
NEUROD1	PRPH	psi-mi:“MI:0915”(physical association)	0.560
KLF11	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560
NEUROD1	NUP58	psi-mi:“MI:0915”(physical association)	0.560
NEUROD1	HTRA2	psi-mi:“MI:0915”(physical association)	0.560
HTT	NEUROD1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (43): EP300 (Reconstituted Complex), NEUROD1 (Affinity Capture-Western), PDHX (Affinity Capture-Western), NEUROD1 (Affinity Capture-Western), TCF4 (Affinity Capture-MS), TCF3 (Affinity Capture-MS), TCF12 (Affinity Capture-MS), DPF3 (Affinity Capture-MS), LACRT (Affinity Capture-MS), NEUROD1 (Affinity Capture-Western), NEUROD1 (Two-hybrid), NEUROD1 (Reconstituted Complex), NEUROD1 (Reconstituted Complex), EP300 (Reconstituted Complex), HAP1 (Two-hybrid)

ESM2 similar proteins: A0A1R3RGK4, A2R6G8, A2T713, A2T7L8, A4IFU7, F1QDF8, G1X9A9, G5EG44, I1S491, O14948, O16850, O16867, O42202, O42261, O42342, O75030, O88368, O93507, P01103, P06876, P19484, P21572, P22980, P38165, P46200, P79766, P80073, Q01663, Q08874, Q13562, Q16534, Q17295, Q28GD5, Q5RFT9, Q5XFQ6, Q60430, Q63302, Q64289, Q64709, Q6DIB4

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, O13125, O13126, O16867, O35437, O42606, O43680, O57598, O60682, O73615

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
NEUROG3	“up-regulates quantity by expression”	NEUROD1	“transcriptional regulation”
NEUROD1	“up-regulates quantity by expression”	MGAT5B	“transcriptional regulation”
NFIA	“up-regulates quantity”	NEUROD1	“transcriptional regulation”
NFIB	“up-regulates quantity”	NEUROD1	“transcriptional regulation”
NFIX	“up-regulates quantity”	NEUROD1	“transcriptional regulation”
MAP3K10	“up-regulates activity”	NEUROD1	binding
HAP1	“up-regulates activity”	NEUROD1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	226
Likely benign	85
Benign	8

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
218145	NM_002500.5(NEUROD1):c.309C>G (p.Arg103=)	Pathogenic
7853	NM_002500.5(NEUROD1):c.332G>T (p.Arg111Leu)	Pathogenic
3027521	NM_002500.5(NEUROD1):c.764C>T (p.Pro255Leu)	Likely pathogenic
3033670	NM_002500.5(NEUROD1):c.341T>A (p.Met114Lys)	Likely pathogenic
4540411	NM_002500.5(NEUROD1):c.328G>C (p.Glu110Gln)	Likely pathogenic

SpliceAI

222 predictions. Top by Δscore:

Variant	Effect	Δscore
2:181679307:T:TA	donor_gain	1.0000
2:181679337:G:C	donor_gain	1.0000
2:181678871:CCTA:C	acceptor_loss	0.9900
2:181678872:CT:C	acceptor_loss	0.9900
2:181678880:A:T	acceptor_gain	0.9900
2:181678882:C:CT	acceptor_gain	0.9900
2:181678883:A:T	acceptor_gain	0.9900
2:181679308:C:A	donor_gain	0.9900
2:181679336:A:AC	donor_gain	0.9900
2:181679336:AG:A	donor_gain	0.9900
2:181680751:T:TA	donor_gain	0.9900
2:181680756:C:A	donor_gain	0.9900
2:181680778:T:TA	donor_gain	0.9900
2:181680779:C:A	donor_gain	0.9900
2:181678868:TTTC:T	acceptor_gain	0.9800
2:181678879:C:CT	acceptor_gain	0.9800
2:181678897:C:CT	acceptor_gain	0.9800
2:181678898:A:T	acceptor_gain	0.9800
2:181680426:TTAC:T	donor_loss	0.9800
2:181680427:TAC:T	donor_loss	0.9800
2:181680428:ACCTT:A	donor_loss	0.9800
2:181680429:C:CA	donor_loss	0.9800
2:181680747:T:TA	donor_gain	0.9800
2:181680755:C:CA	donor_gain	0.9800
2:181678869:TTC:T	acceptor_gain	0.9700
2:181678870:TC:T	acceptor_gain	0.9700
2:181678871:CC:C	acceptor_gain	0.9700
2:181678872:C:CC	acceptor_gain	0.9700
2:181678876:A:C	acceptor_gain	0.9700
2:181679729:C:A	donor_gain	0.9700

AlphaMissense

2368 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:181678292:A:G	L190P	1.000
2:181678298:A:G	L188P	1.000
2:181678304:C:T	G186D	1.000
2:181678305:C:G	G186R	1.000
2:181678307:G:T	A185E	1.000
2:181678308:C:G	A185P	1.000
2:181678310:A:T	V184D	1.000
2:181678313:A:G	L183P	1.000
2:181678313:A:T	L183Q	1.000
2:181678315:G:C	N182K	1.000
2:181678315:G:T	N182K	1.000
2:181678322:G:A	T180I	1.000
2:181678322:G:T	T180N	1.000
2:181678331:G:A	S177F	1.000
2:181678331:G:T	S177Y	1.000
2:181678334:A:G	L176S	1.000
2:181678338:C:G	G175R	1.000
2:181678342:G:C	C173W	1.000
2:181678343:C:T	C173Y	1.000
2:181678344:A:G	C173R	1.000
2:181678346:A:G	L172P	1.000
2:181678346:A:T	L172H	1.000
2:181678355:A:T	V169D	1.000
2:181678357:G:C	F168L	1.000
2:181678357:G:T	F168L	1.000
2:181678358:A:G	F168S	1.000
2:181678359:A:G	F168L	1.000
2:181678391:A:G	L157P	1.000
2:181678401:A:G	S154P	1.000
2:181678403:A:G	L153P	1.000

dbSNP variants (sampled 300 via entrez): RS1000553605 (2:181679376 C>T), RS1000806031 (2:181671350 G>T), RS1000858388 (2:181671053 A>C), RS1001265596 (2:181673546 C>A), RS1001325253 (2:181678718 G>T), RS1001448496 (2:181672559 C>T), RS1001465499 (2:181680139 G>T), RS1001754291 (2:181673286 T>C), RS1001926721 (2:181673325 G>T), RS1002417245 (2:181679108 A>G), RS1002671995 (2:181671897 C>T), RS1002738274 (2:181668364 T>C), RS1003140709 (2:181681118 G>A,T), RS1003340889 (2:181675357 G>A), RS1003392095 (2:181668796 G>A,T)

Disease associations

OMIM: gene MIM:601724 | disease phenotypes: MIM:125853, MIM:606394, MIM:125850, MIM:606391

GenCC curated gene-disease

Disease	Classification	Inheritance
maturity-onset diabetes of the young type 6	Strong	Autosomal recessive
permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	Strong	Autosomal recessive
complex neurodevelopmental disorder	Moderate	Autosomal recessive
monogenic diabetes	Moderate	Autosomal recessive
maturity-onset diabetes of the young	Supportive	Autosomal dominant
retinitis pigmentosa	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
monogenic diabetes	Moderate	AD
monogenic diabetes	Moderate	AR

Mondo (8): type 2 diabetes mellitus (MONDO:0005148), maturity-onset diabetes of the young type 6 (MONDO:0011668), monogenic diabetes (MONDO:0015967), inherited retinal dystrophy (MONDO:0019118), maturity-onset diabetes of the young (MONDO:0018911), complex neurodevelopmental disorder (MONDO:0100038), permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome (MONDO:0012192), retinitis pigmentosa (MONDO:0019200)

Orphanet (3): MODY (Orphanet:552), Rare genetic diabetes mellitus (Orphanet:183625), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000077	Abnormality of the kidney
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000119	Abnormality of the genitourinary system
HP:0000488	Retinopathy
HP:0000825	Hyperinsulinemic hypoglycemia
HP:0000831	Insulin-resistant diabetes mellitus
HP:0000855	Insulin resistance
HP:0000956	Acanthosis nigricans
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001520	Large for gestational age
HP:0001738	Exocrine pancreatic insufficiency
HP:0001952	Glucose intolerance
HP:0001953	Diabetic ketoacidosis
HP:0001998	Neonatal hypoglycemia
HP:0002594	Pancreatic hypoplasia
HP:0003074	Hyperglycemia
HP:0003076	Glycosuria
HP:0003584	Late onset
HP:0004904	Maturity-onset diabetes of the young
HP:0004924	Abnormal oral glucose tolerance
HP:0005978	Type II diabetes mellitus
HP:0008255	Transient neonatal diabetes mellitus
HP:0012028	Hepatocellular adenoma
HP:0025502	Overweight
HP:0030057	Autoimmune antibody positivity
HP:0030794	Abnormal circulating C-peptide concentration
HP:0031819	Increased waist to hip ratio

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008605_6	Glucosuria (moderate to severe)	1.000000e-10
GCST008614_2	Glucosuria	6.000000e-10

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C563796	Diabetes Mellitus, Permanent Neonatal, with Cerebellar Agenesis (supp.)
C565231	MODY, Type 6 (supp.)
C562772	Mason-Type Diabetes (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1801262	Efficacy	3	repaglinide	Diabetes Mellitus

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801262	NEUROD1	3	4.00	1	repaglinide

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	5
Tretinoin	increases expression	2
Valproic Acid	affects expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
arsenite	increases methylation	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
imeglimin	increases expression	1
Aripiprazole	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Carbamazepine	affects expression	1
Fluorouracil	affects expression	1
Methylmercury Compounds	decreases expression	1
Rotenone	increases expression	1
Antirheumatic Agents	decreases expression	1
Polyethylene	decreases expression	1

Cellosaurus cell lines

6 cell lines: 4 embryonic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A4K0	SEES3-1V human NEUROD1, clone1	Embryonic stem cell	Male
CVCL_A4K1	SEES3-1V human NEUROD1, clone2	Embryonic stem cell	Male
CVCL_A4K2	SEES3-1V human NEUROD1, clone3	Embryonic stem cell	Male
CVCL_E3V6	HB1.F3.NeuroD	Transformed cell line	Female
CVCL_XA17	MEL-1 INSGFP/w NEUROD1(-/-)	Embryonic stem cell	Male
CVCL_YB08	EndoC-betaH1 NEUROD1-KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	PHASE4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes