NEURL2

Summary

NEURL2 (neuralized E3 ubiquitin protein ligase 2, HGNC:16156) is a protein-coding gene on chromosome 20q13.12, encoding Neuralized-like protein 2 (Q9BR09). Plays an important role in the process of myofiber differentiation and maturation.

This gene encodes a protein that is involved in the regulation of myofibril organization. This protein is likely the adaptor component of the E3 ubiquitin ligase complex in striated muscle, and it regulates the ubiquitin-mediated degradation of beta-catenin during myogenesis. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 140825 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_080749

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16156
Approved symbol	NEURL2
Name	neuralized E3 ubiquitin protein ligase 2
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ337O18.6, FLJ30259, Ozz, Ozz-E3
Ensembl gene	ENSG00000124257
Ensembl biotype	protein_coding
OMIM	608597
Entrez	140825

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000372518, ENST00000545238

RefSeq mRNA: 2 — MANE Select: NM_080749 NM_001278535, NM_080749

CCDS: CCDS13384

Canonical transcript exons

ENST00000372518 — 2 exons

Exon	Start	End
ENSE00001458001	45888634	45888873
ENSE00001458004	45890250	45891208

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 94.70.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7910 / max 54.2742, expressed in 443 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187496	0.3972	209
187497	0.3938	165

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.70	gold quality
apex of heart	UBERON:0002098	87.08	gold quality
mucosa of stomach	UBERON:0001199	84.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.87	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.60	gold quality
tendon of biceps brachii	UBERON:0008188	83.18	silver quality
thymus	UBERON:0002370	82.99	gold quality
muscle of leg	UBERON:0001383	81.91	gold quality
gastrocnemius	UBERON:0001388	81.89	gold quality
right adrenal gland cortex	UBERON:0035827	81.52	gold quality
quadriceps femoris	UBERON:0001377	81.38	silver quality
vastus lateralis	UBERON:0001379	80.97	silver quality
right adrenal gland	UBERON:0001233	80.21	gold quality
left ovary	UBERON:0002119	79.61	gold quality
right ovary	UBERON:0002118	79.58	gold quality
left adrenal gland	UBERON:0001234	79.29	gold quality
right coronary artery	UBERON:0001625	79.13	gold quality
omental fat pad	UBERON:0010414	79.01	gold quality
right lobe of liver	UBERON:0001114	78.99	gold quality
left coronary artery	UBERON:0001626	78.96	gold quality
peritoneum	UBERON:0002358	78.94	gold quality
left uterine tube	UBERON:0001303	78.88	gold quality
left adrenal gland cortex	UBERON:0035825	78.43	gold quality
heart left ventricle	UBERON:0002084	78.33	gold quality
lower esophagus	UBERON:0013473	78.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	78.28	gold quality
metanephros cortex	UBERON:0010533	78.10	gold quality
right atrium auricular region	UBERON:0006631	78.04	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.01	gold quality
coronary artery	UBERON:0001621	77.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting NEURL2, 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-4283	100.00	66.42	2097
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-548Q	98.71	65.35	563
HSA-MIR-1-5P	98.70	68.66	1017
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-4522	95.76	66.23	742
HSA-MIR-11400	94.03	67.12	81

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	neurl2	ENSDARG00000062446
mus_musculus	Neurl2	ENSMUSG00000039873

Protein

Protein identifiers

Neuralized-like protein 2 — Q9BR09 (reviewed: Q9BR09)

All UniProt accessions (2): H0YGA6, Q9BR09

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the process of myofiber differentiation and maturation. Probable substrate-recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of proteins. Probably contributes to catalysis through recognition and positioning of the substrate and the ubiquitin-conjugating enzyme. During myogenesis, controls the ubiquitination and degradation of the specific pool of CTNNB1/beta-catenin located at the sarcolemma.

Subunit / interactions. Probable component the ECS(NEURL2) E3 ubiquitin-protein ligase complex consisting of ELOB/Elongin B, ELOC/Elongin C, CUL5, RBX1 and NEURL2. Interacts with CTNNB1.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed specifically in skeletal and cardiac muscles.

Domain organisation. The SOCS domain mediates the interaction with ELOB and ELOC, while the NHR domain may be involved in ubiquitination substrate binding.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (2): NP_001265464, NP_542787* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001496	SOCS_box	Domain
IPR006573	NHR_dom	Domain
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR037962	Neuralized	Family
IPR043136	B30.2/SPRY_sf	Homologous_superfamily

Pfam: PF07177, PF07525

UniProt features (5 total): domain 2, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BR09-F1	83.30	0.53

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8951664	Neddylation
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 106 (showing top): BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AP2_Q3, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_ACTOMYOSIN_STRUCTURE_ORGANIZATION, GOBP_ORGANELLE_ASSEMBLY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, PU1_Q6, RYTTCCTG_ETS2_B, RGAGGAARY_PU1_Q6, GOBP_MUSCLE_CELL_DEVELOPMENT, GOBP_MUSCLE_CELL_DIFFERENTIATION, MYCMAX_03, GOMF_ACYLTRANSFERASE_ACTIVITY

GO Biological Process (2): protein ubiquitination (GO:0016567), intracellular signal transduction (GO:0035556)

GO Molecular Function (1): ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
protein modification by small protein conjugation	1
signal transduction	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
cytoplasm	1

Protein interactions and networks

STRING

384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEURL2	SPATA25	Q9BR10	678
NEURL2	CISH	Q9NSE2	647
NEURL2	ZSWIM1	Q9BR11	541
NEURL2	CTNNB1	P35222	488
NEURL2	ASB5	Q8WWX0	487
NEURL2	WFDC10B	Q8IUB3	480
NEURL2	ZNF335	Q9H4Z2	446
NEURL2	ACOT8	O14734	439
NEURL2	CALHM2	Q9HA72	432
NEURL2	TRIM54	Q9BYV2	430
NEURL2	SNX21	Q969T3	430
NEURL2	ACSS3	Q9H6R3	404
NEURL2	NEURL1	O76050	402
NEURL2	WFDC3	Q8IUB2	394
NEURL2	JADE1	Q6IE81	370
NEURL2	PCIF1	Q9H4Z3	370

IntAct

0 interactions, top by confidence:

BioGRID (10): NEURL2 (Positive Genetic), NEURL2 (Affinity Capture-Western), SMN1 (Biochemical Activity), UBE2H (Reconstituted Complex), NEURL2 (Negative Genetic), NEURL2 (Reconstituted Complex), NEURL2 (Reconstituted Complex), CTNNB1 (Biochemical Activity), MYH6 (Biochemical Activity), PDCD6IP (Biochemical Activity)

ESM2 similar proteins: A5PJU7, A8MQ27, F1MLB4, F1MX48, F1SAM7, I3L5V6, O75425, O95382, P36916, Q08DG4, Q0MW30, Q14451, Q2YD98, Q32P44, Q3MIP1, Q3T033, Q3UPE3, Q3UV16, Q505F5, Q5EBM0, Q5U651, Q5ZM20, Q641Q3, Q6MG06, Q6SZW1, Q6ZTW0, Q7T0L4, Q8BGG6, Q8BH83, Q8C0R7, Q8K0Y7, Q8N9W5, Q8R2K4, Q8TE68, Q8VC03, Q96BM1, Q96E14, Q96EF6, Q96EY9, Q99JB7

Diamond homologs: A8MQ27, O60291, O76050, Q0MW30, Q0WS06, Q3TEL6, Q4FE47, Q557E7, Q5M870, Q5XIQ4, Q6INH1, Q6R7D2, Q7ZUL9, Q84ME1, Q8CJC5, Q8VCM5, Q923S6, Q94HV7, Q96EH8, Q96PX1, Q9BR09, Q9D074, Q9D0S4, P29503, Q24746, A1L3F4, Q69Z36, Q6ZN04, Q6ZQM0, Q8CIN9, Q8WZ73, Q05A36, Q3UE17, Q5NCX5, Q5U5Q3, Q7M3S9, Q8LA32, Q99675, Q9FPH0, Q9LYW5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

184 predictions. Top by Δscore:

Variant	Effect	Δscore
20:45890248:A:AC	donor_gain	1.0000
20:45890249:C:CC	donor_gain	1.0000
20:45890248:ACAG:A	donor_gain	0.9900
20:45890249:CAG:C	donor_gain	0.9900
20:45890249:CAGC:C	donor_gain	0.9900
20:45890256:A:AC	donor_gain	0.9900
20:45890257:C:CC	donor_gain	0.9900
20:45890304:C:CT	donor_gain	0.9900
20:45890305:C:CT	donor_gain	0.9900
20:45888869:TGGCA:T	acceptor_gain	0.9800
20:45888872:CA:C	acceptor_gain	0.9800
20:45888874:C:CC	acceptor_gain	0.9800
20:45888870:GGCA:G	acceptor_gain	0.9700
20:45890246:CTAC:C	donor_loss	0.9700
20:45890247:TA:T	donor_loss	0.9700
20:45890249:CA:C	donor_gain	0.9700
20:45888871:GCA:G	acceptor_gain	0.9600
20:45888872:CAC:C	acceptor_gain	0.9600
20:45888873:AC:A	acceptor_loss	0.9600
20:45888874:C:A	acceptor_loss	0.9600
20:45888875:T:G	acceptor_loss	0.9600
20:45890248:ACAGC:A	donor_gain	0.9600
20:45890249:CAGCC:C	donor_gain	0.9600
20:45890277:CGCT:C	donor_gain	0.9500
20:45890300:TCC:T	donor_gain	0.9400
20:45888885:AGA:A	acceptor_gain	0.9300
20:45890300:T:TA	donor_gain	0.9200
20:45888883:GAAGA:G	acceptor_gain	0.9100
20:45890243:TAC:T	donor_loss	0.9100
20:45888884:AAGA:A	acceptor_gain	0.9000

AlphaMissense

1826 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:45890845:G:C	F49L	0.999
20:45890845:G:T	F49L	0.999
20:45890847:A:G	F49L	0.999
20:45890293:A:C	F233L	0.998
20:45890293:A:T	F233L	0.998
20:45890295:A:G	F233L	0.998
20:45890824:G:C	S56R	0.998
20:45890824:G:T	S56R	0.998
20:45890826:T:G	S56R	0.998
20:45890365:G:C	N209K	0.997
20:45890365:G:T	N209K	0.997
20:45890366:T:A	N209I	0.997
20:45890763:A:G	W77R	0.997
20:45890763:A:T	W77R	0.997
20:45890795:A:G	F66S	0.997
20:45890828:A:G	F55S	0.997
20:45890859:G:T	R45S	0.997
20:45890300:T:A	D231V	0.996
20:45890417:A:T	V192D	0.996
20:45890756:C:T	G79E	0.996
20:45890761:C:A	W77C	0.996
20:45890761:C:G	W77C	0.996
20:45890789:A:T	V68D	0.996
20:45890846:A:C	F49C	0.996
20:45890915:A:G	F26S	0.996
20:45890295:A:T	F233I	0.995
20:45890301:C:A	D231Y	0.995
20:45890301:C:G	D231H	0.995
20:45890738:A:G	L85P	0.995
20:45890742:C:G	G84R	0.995

dbSNP variants (sampled 300 via entrez): RS1000460046 (20:45889581 T>A), RS1000947010 (20:45889848 A>G), RS1001455876 (20:45890406 G>A,T), RS1003060294 (20:45889154 T>G), RS1003334266 (20:45889358 T>C), RS1003805541 (20:45891628 G>A,T), RS1005121712 (20:45889434 C>A,T), RS1005269664 (20:45889137 T>C), RS1005794566 (20:45892064 G>C), RS1005907488 (20:45890456 T>A), RS1006542703 (20:45890781 C>T), RS1006892424 (20:45891540 G>A,C), RS1007018466 (20:45891561 T>C,G), RS1007716066 (20:45891118 G>A,T), RS1007752268 (20:45890883 C>A,G,T)

Disease associations

OMIM: gene MIM:608597 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Nickel	increases expression	2
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Smoke	decreases expression	1
Triclosan	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
S-Nitrosoglutathione	affects expression	1

Clinical trials (associated diseases)

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