ISL1

Summary

ISL1 (ISL LIM homeobox 1, HGNC:6132) is a protein-coding gene on chromosome 5q11.1, encoding Insulin gene enhancer protein ISL-1 (P61371). DNA-binding transcriptional activator.

This gene encodes a member of the LIM/homeodomain family of transcription factors. The encoded protein binds to the enhancer region of the insulin gene, among others, and may play an important role in regulating insulin gene expression. The encoded protein is central to the development of pancreatic cell lineages and may also be required for motor neuron generation. Mutations in this gene have been associated with maturity-onset diabetes of the young.

Source: NCBI Gene 3670 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart disease (Definitive, ClinGen)
• GWAS associations: 25
• Clinical variants (ClinVar): 115 total
• Phenotypes (HPO): 13
• Transcription factor: yes — 48 downstream targets (CollecTRI)
• MANE Select transcript: NM_002202

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6132
Approved symbol	ISL1
Name	ISL LIM homeobox 1
Location	5q11.1
Locus type	gene with protein product
Status	Approved
Aliases	Isl-1, ISLET1
Ensembl gene	ENSG00000016082
Ensembl biotype	protein_coding
OMIM	600366
Entrez	3670

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000230658, ENST00000505475, ENST00000511384, ENST00000967706

RefSeq mRNA: 1 — MANE Select: NM_002202 NM_002202

CCDS: CCDS43314

Canonical transcript exons

ENST00000230658 — 6 exons

Exon	Start	End
ENSE00000478749	51384541	51384730
ENSE00000743029	51391274	51391441
ENSE00001002260	51393494	51394730
ENSE00001002261	51383448	51383699
ENSE00003699949	51387490	51387749
ENSE00003700522	51389646	51389932

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 93.11.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8459 / max 447.6277, expressed in 409 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56378	1.8071	407
56379	0.0388	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.11	gold quality
cervix squamous epithelium	UBERON:0006922	91.69	gold quality
islet of Langerhans	UBERON:0000006	91.46	gold quality
penis	UBERON:0000989	90.47	gold quality
oocyte	CL:0000023	90.46	gold quality
urethra	UBERON:0000057	89.96	gold quality
pylorus	UBERON:0001166	88.81	gold quality
cardia of stomach	UBERON:0001162	88.70	gold quality
sperm	CL:0000019	86.60	silver quality
buccal mucosa cell	CL:0002336	86.58	gold quality
pancreatic ductal cell	CL:0002079	86.14	silver quality
mucosa of stomach	UBERON:0001199	85.91	gold quality
vagina	UBERON:0000996	85.75	gold quality
seminal vesicle	UBERON:0000998	85.58	gold quality
epithelial cell of pancreas	CL:0000083	84.94	silver quality
male germ cell	CL:0000015	83.49	silver quality
prostate gland	UBERON:0002367	82.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.97	gold quality
cervix epithelium	UBERON:0004801	81.72	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.36	gold quality
type B pancreatic cell	CL:0000169	81.25	silver quality
body of stomach	UBERON:0001161	79.89	gold quality
stomach	UBERON:0000945	79.73	gold quality
fundus of stomach	UBERON:0001160	79.35	gold quality
mammalian vulva	UBERON:0000997	79.24	gold quality
ectocervix	UBERON:0012249	78.80	gold quality
placenta	UBERON:0001987	77.02	gold quality
dorsal root ganglion	UBERON:0000044	75.27	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.63	gold quality
uterine cervix	UBERON:0000002	74.59	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	1044.69
E-HCAD-56	yes	851.90
E-MTAB-8894	yes	668.46
E-MTAB-7008	yes	43.68
E-MTAB-7316	yes	39.28
E-HCAD-5	yes	19.84
E-MTAB-5061	yes	11.48
E-GEOD-83139	yes	9.63
E-GEOD-93593	yes	9.43
E-ANND-3	yes	8.53
E-MTAB-9388	yes	8.36
E-HCAD-10	yes	5.63
E-GEOD-81547	yes	5.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

48 targets.

Target	Regulation
ADAM2
ARX
ATOH7	Unknown
BARX1	Unknown
BHLHE23	Unknown
CAPS2
CCND1	Unknown
CD74
DLST
FGF10	Unknown
FSHB	Activation
GAL
GCG	Unknown
GHRL
GIP
GLS2
GNRHR
HNF1A	Activation
HNF4A
IAPP
INS	Activation
ISL1
KCNJ11	Activation
LDB1
LHB
LHX1	Repression
MEF2C	Activation
MYC	Unknown
NEUROD1	Activation
NEUROD4

Upstream regulators (CollecTRI, top): AHR, ATOH7, CTNNB1, HOXC6, ISL1, MYC, PAX4, PHOX2B, POU2F1, RARB, SOX2

miRNA regulators (miRDB)

105 targeting ISL1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
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-4482-3P	99.98	72.50	3147
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343

Literature-anchored findings (GeneRIF, showing 40)

• Seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions of ISL1 GENE. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families. (PMID:15161765)
• we demonstrated that ISL1 and BETA2 could activate insulin gene transcription synergistically. (PMID:16321656)
• cultured pancreatic islets contain nestin and Isl-1 positive mesenchymal stem cells with multipotential developmental capacity (PMID:16713999)
• Isl1 could enhance the HNF4alpha-mediated activation of transcription of the HNF1alpha, PPARalpha and insulin I promoters (PMID:17022998)
• Sudy illustrated that GPA2 is positively regulated by isl-1, suggesting that this protein associates with endocrine systems including the pituitary and pancreas. (PMID:17363077)
• beta-catenin signaling regulates proliferation and survival of cardiac progenitors (PMID:17519333)
• An important developmental and regulatory gene ISL1 is uniquely expressed in visceral fat, probably in the preadipocyte. ISL1 may be regulated by adiposity. (PMID:18239644)
• Although the LIM interaction domain of Ldb1 (Ldb1(LID)) and Isl1(LBD) share low levels of sequence homology, X-ray and NMR structures reveal that they bind Lhx3 in an identical manner, that is, Isl1(LBD) mimics Ldb1(LID). (PMID:18583962)
• purified ISL1(+) primordial progenitors are capable of self-renewal and expansion before differentiation into the three major cell types in the heart (PMID:19571884)
• 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)
• early first trimester human embryonic heart expresses clusters of Isl1(+)cells, some of which differentiate into cardiomyocytes. (PMID:19896915)
• Two different ISL1 haplotypes contribute to risk of congenital heart disease in white and black/African American populations. (PMID:20520780)
• Data indicate that, despite the relevant role of ISL1 in thyroid and heart morphogenesis, mutations in its coding region are not associated with TD in our group of patients. (PMID:21060249)
• Gastrin-positive neuroendocrine tumors, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). (PMID:21739268)
• This study establishes ISL1 as a novel transcriptional regulator of LHX3 and describes a potential mechanism for regulation by PITX1. (PMID:22194342)
• The relationship between human ISL1 and FGF10 within the embryonic time window during which the linear heart tube remodels into four chambers, was examined. (PMID:22303449)
• Both Islet 1 and PAX8 are reliable immunohistochemical markers for identifying metastatic neuroendocrine tumors of pancreatic origin. (PMID:22388755)
• This is the first study which indicates that ISL1 common variant rs1017 may not play a role in sporadic CHD susceptibility in the Chinese population. (PMID:22480195)
• This study describes a new gain-of-function p.Asn252Ser variant in the human ISL1 gene, which could potentially lead to greater activation of downstream targets involved in cardiac development, dilation, and hypertrophy. (PMID:23152444)
• ISL1 common variant rs1017 is not associated with increased genetic risk of CHD in the white population. (PMID:23229290)
• Our findings confirm that Isl1 is a sensitive marker of pancreatic origin in cases of metastatic neuroendocrine neoplasms . (PMID:23348208)
• The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels (PMID:23436614)
• findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed. (PMID:23503646)
• The findings suggest that ISL1 genetic polymorphisms are associated with occurrence of VSD, thus they may be useful as molecular markers for prediction of VSD. (PMID:23572340)
• Overexpression of VEGF-A promotes not only the endothelial specification but also engraftment, proliferation and survival (reduced apoptosis) of the human Isl1+ progenitors in vivo. (PMID:24018375)
• We have demonstrated that Islet 1 and PAX8 are not entirely specific for neuroendocrine tumors of pancreatic origin, as they are expressed in a majority of rectal neuroendocrine tumors. (PMID:24037217)
• Haplotype TT of ISL1 may increase the risk of congenital heart disease (CHD)in Tianjin Han children. (PMID:24131831)
• Overexpression of ISL1 in human mesnchymal stem cells promotes angiogenesis in vitro and in vivo through increasing secretion of MCP3 and other paracrine factors. (PMID:24578274)
• Results suggest that rs1017 ISL1 contributed to the risk of Congenital heart disease (CHD) in Chinese Han people, and the gene may be involved in the formation and development of the heart. (PMID:24634231)
• This study demonstrates that the Isl1-Gata3 transcription regulatory axis is essential for normal pyloric development. (PMID:24674670)
• ISL1 is commonly expressed in rhabdomyosarcoma, particularly the alveolar subtype (PMID:24751901)
• these results demonstrate a positive feedback regulation of ISL-1 in diffuse large B cell lymphoma but not in pancreatic beta-cells, which might result in the functional diversities of ISL-1 in different physiological and pathological processes. (PMID:24845569)
• Tcf7l2 is regulating proinsulin expression directly via Isl1, Ins1 and indirectly via MafA, NeuroD1 and Pdx1. (PMID:25015099)
• ISL-1 is tightly linked to non-Hodgkin lymphoma proliferation and development by promoting c-Myc transcription, and its aberrant expression was regulated by p-STAT3/p-c-Jun/ISL-1 complex activation. (PMID:25070240)
• Isl1 overexpression in embryonic stem cells results in normal electrophysiologically functioning cells. (PMID:25524439)
• The present study identified the first genome-wide significant locus for classic bladder exstrophy at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region. (PMID:25763902)
• In bladder exstrophy there is a clear correlation with the a mutation of the chromosome 5 ISL1 (5q11.1) gene. (PMID:26077299)
• Suggest that ISL-1 may be a useful prognostic biomarker and may represent a novel therapeutic target for gastric adenocarcinoma. (PMID:26142548)
• Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (PMID:26332997)
• SSBP3 Interacts With Islet-1 and Ldb1 to Impact Pancreatic beta-Cell Target Genes (PMID:26495868)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	isl1a	ENSDARG00000004023
mus_musculus	Isl1	ENSMUSG00000042258
rattus_norvegicus	Isl1	ENSRNOG00000012556
drosophila_melanogaster	tup	FBGN0003896
caenorhabditis_elegans	lim-7	WBGENE00002989

Paralogs (1): ISL2 (ENSG00000159556)

Protein

Protein identifiers

Insulin gene enhancer protein ISL-1 — P61371 (reviewed: P61371)

All UniProt accessions (2): P61371, D6RBJ1

UniProt curated annotations — full annotation on UniProt →

Function. DNA-binding transcriptional activator. Recognizes and binds to the consensus octamer binding site 5’-ATAATTAA-3’ in promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Cooperates with the transcription factor POU4F2 to achieve maximal levels of expression of RGC target genes and RGC fate specification in the developing retina. Involved in the specification of motor neurons in cooperation with LHX3 and LDB1. Binds to insulin gene enhancer sequences. Essential for heart development. Marker of one progenitor cell population that give rise to the outflow tract, right ventricle, a subset of left ventricular cells, and a large number of atrial cells as well, its function is required for these progenitors to contribute to the heart. Controls the expression of FGF and BMP growth factors in this cell population and is required for proliferation and survival of cells within pharyngeal foregut endoderm and adjacent splanchnic mesoderm as well as for migration of cardiac progenitors into the heart.

Subunit / interactions. At neuronal promoters, displaces LDB1 from LHX3 LIM domain to form a ternary complex in which ISL1 contacts both LHX3 and LDB1; allosteric structural changes in the DNA binding domain of LHX3, induced by the ISL1:LHX3 interaction, may explain differences in sequence specificity of the different complexes. Interacts with LHX3. Interacts (via C-terminus) with POU4F2 (via C-terminus) isoform 1. Interacts with POU3F2. Interacts with POU4F3. Interacts (via N-terminal domain) with MLIP; the interaction represses ISL1 transactivator activity. Interacts with GCN5/KAT2A. Interactions of ISL1 with MLIP1 or KAT2A may be mutually exclusive.

Subcellular location. Nucleus.

Tissue specificity. Expressed in subsets of neurons of the adrenal medulla and dorsal root ganglion, inner nuclear and ganglion cell layers in the retina, the pineal and some regions of the brain.

Post-translational modifications. Ubiquitinated probably by WWP1 E3 ubiquitin ligase; ubiquitination is followed by protein degradation. Phosphorylated.

RefSeq proteins (1): NP_002193* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001781	Znf_LIM	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR047169	ISL1/2-like	Family
IPR047244	ISL1/2-like_LIM1	Domain

Pfam: PF00046, PF00412

UniProt features (7 total): domain 2, region of interest 2, chain 1, DNA-binding region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61371-F1	72.57	0.37

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-400511	Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9733709	Cardiogenesis
R-HSA-1266738	Developmental Biology
R-HSA-2980736	Peptide hormone metabolism
R-HSA-376176	Signaling by ROBO receptors
R-HSA-392499	Metabolism of proteins
R-HSA-400508	Incretin synthesis, secretion, and inactivation
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 557 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT

GO Biological Process (70): negative regulation of transcription by RNA polymerase II (GO:0000122), neural crest cell migration (GO:0001755), secondary heart field specification (GO:0003139), outflow tract septum morphogenesis (GO:0003148), outflow tract morphogenesis (GO:0003151), endocardial cushion morphogenesis (GO:0003203), cardiac right ventricle morphogenesis (GO:0003215), regulation of secondary heart field cardioblast proliferation (GO:0003266), transcription by RNA polymerase II (GO:0006366), axonogenesis (GO:0007409), heart development (GO:0007507), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of epithelial to mesenchymal transition (GO:0010718), spinal cord motor neuron cell fate specification (GO:0021520), spinal cord motor neuron differentiation (GO:0021522), visceral motor neuron differentiation (GO:0021524), trigeminal nerve development (GO:0021559), pituitary gland development (GO:0021983), pancreas development (GO:0031016), axon regeneration (GO:0031103), retinal ganglion cell axon guidance (GO:0031290), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of insulin secretion (GO:0032024), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-1 alpha production (GO:0032730), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of intracellular estrogen receptor signaling pathway (GO:0033147), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of cell differentiation (GO:0045597), negative regulation of neuron differentiation (GO:0045665), positive regulation of angiogenesis (GO:0045766), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of transcription by RNA polymerase II (GO:0045944), neuron fate specification (GO:0048665)

GO Molecular Function (18): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), core promoter sequence-specific DNA binding (GO:0001046), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), nuclear receptor binding (GO:0016922), LIM domain binding (GO:0030274), nuclear estrogen receptor binding (GO:0030331), bHLH transcription factor binding (GO:0043425), metal ion binding (GO:0046872), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), transcription cis-regulatory region binding (GO:0000976), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Developmental Biology	2
Incretin synthesis, secretion, and inactivation	1
Signaling by ROBO receptors	1
Metabolism of proteins	1
Axon guidance	1
Peptide hormone metabolism	1
Nervous system development	1

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
heart morphogenesis	2
spinal cord motor neuron differentiation	2
transcription cis-regulatory region binding	2
DNA-binding transcription factor binding	2
binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
neural crest cell development	1
mesenchymal cell migration	1
heart field specification	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
anatomical structure morphogenesis	1
endocardial cushion development	1
mesenchyme morphogenesis	1
cardiac ventricle morphogenesis	1
regulation of cardioblast proliferation	1
DNA-templated transcription	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
animal organ development	1
circulatory system development	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
neuron fate specification	1
cell differentiation in spinal cord	1
ventral spinal cord development	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

59 interactions, top by confidence:

A	B	Type	Score
ZNF511	ISL1	psi-mi:“MI:0915”(physical association)	0.780
ISL1	ZNF511	psi-mi:“MI:0915”(physical association)	0.780
ISL1	LHX4	psi-mi:“MI:0915”(physical association)	0.750
SSBP3	LMX1B	psi-mi:“MI:0914”(association)	0.740
PYGO1	BCL9	psi-mi:“MI:0914”(association)	0.700
ISL1	SSBP4	psi-mi:“MI:0915”(physical association)	0.660
SYNGAP1	ISL1	psi-mi:“MI:0915”(physical association)	0.620
SSBP3	LHX1	psi-mi:“MI:0914”(association)	0.570
ISL1	ADH7	psi-mi:“MI:0915”(physical association)	0.560
ADH7	ISL1	psi-mi:“MI:0915”(physical association)	0.560
ISL1	LDB1	psi-mi:“MI:0915”(physical association)	0.560
SSBP2	CLEC18A	psi-mi:“MI:0914”(association)	0.530
LHX4	THAP12	psi-mi:“MI:0914”(association)	0.530
ARIH1	SPOP	psi-mi:“MI:0914”(association)	0.530
SSBP4	GM2A	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	SEC16A	psi-mi:“MI:0914”(association)	0.530
SSBP4	LMX1B	psi-mi:“MI:0914”(association)	0.530
GMNN	ISL1	psi-mi:“MI:0407”(direct interaction)	0.440
ISL1	CDK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PLCG2	ISL1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (62): ZNF511 (Two-hybrid), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Two-hybrid), ISL1 (Two-hybrid), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-Western), ISL1 (Affinity Capture-Western), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS), ISL1 (Affinity Capture-MS)

ESM2 similar proteins: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, G5EEA1, P20154, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53411, P53412, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q1LWV4, Q5IS44, Q5IS89, Q68EY3

Diamond homologs: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, O14639, O35652, O60663, O88609, O94929, O97581, P20154, P25791, P25800, P25801, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50480, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53410, P53411, P53412, P53413, P53667, P53668

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ISL1	“form complex”	NLI/Lmx1.1/Isl1	binding
LHX3	“up-regulates activity”	ISL1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	52
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

935 predictions. Top by Δscore:

Variant	Effect	Δscore
5:51383700:G:GG	donor_gain	1.0000
5:51384726:ATCAG:A	donor_loss	1.0000
5:51384727:TCAGG:T	donor_loss	1.0000
5:51384728:CAGG:C	donor_loss	1.0000
5:51384729:AGGT:A	donor_loss	1.0000
5:51384730:GG:G	donor_loss	1.0000
5:51384731:GT:G	donor_loss	1.0000
5:51384732:T:G	donor_loss	1.0000
5:51389644:A:AG	acceptor_gain	1.0000
5:51389644:AGC:A	acceptor_gain	1.0000
5:51389645:G:GG	acceptor_gain	1.0000
5:51389645:GCG:G	acceptor_gain	1.0000
5:51389928:AAACT:A	donor_gain	1.0000
5:51389929:AACT:A	donor_gain	1.0000
5:51389930:ACT:A	donor_gain	1.0000
5:51389930:ACTGT:A	donor_loss	1.0000
5:51389931:CT:C	donor_gain	1.0000
5:51389932:TG:T	donor_loss	1.0000
5:51389933:G:GA	donor_loss	1.0000
5:51389933:G:GG	donor_gain	1.0000
5:51383697:AAAGT:A	donor_loss	0.9900
5:51383699:AGTA:A	donor_loss	0.9900
5:51383700:GTA:G	donor_loss	0.9900
5:51383701:T:A	donor_loss	0.9900
5:51384657:AATC:A	donor_gain	0.9900
5:51384658:ATCA:A	donor_gain	0.9900
5:51387489:GGTT:G	acceptor_gain	0.9900
5:51389644:AGCG:A	acceptor_gain	0.9900
5:51389645:GC:G	acceptor_gain	0.9900
5:51389645:GCGG:G	acceptor_gain	0.9900

AlphaMissense

2321 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:51384561:T:A	C17S	1.000
5:51384561:T:C	C17R	1.000
5:51384562:G:A	C17Y	1.000
5:51384562:G:C	C17S	1.000
5:51384562:G:T	C17F	1.000
5:51384563:T:G	C17W	1.000
5:51384567:G:C	G19R	1.000
5:51384568:G:A	G19D	1.000
5:51384570:T:A	C20S	1.000
5:51384570:T:C	C20R	1.000
5:51384571:G:A	C20Y	1.000
5:51384571:G:C	C20S	1.000
5:51384571:G:T	C20F	1.000
5:51384572:C:G	C20W	1.000
5:51384583:T:A	I24N	1.000
5:51384583:T:C	I24T	1.000
5:51384583:T:G	I24S	1.000
5:51384589:A:T	D26V	1.000
5:51384601:T:A	L30Q	1.000
5:51384601:T:C	L30P	1.000
5:51384607:T:A	V32D	1.000
5:51384624:T:A	W38R	1.000
5:51384624:T:C	W38R	1.000
5:51384625:G:C	W38S	1.000
5:51384625:G:T	W38L	1.000
5:51384626:G:C	W38C	1.000
5:51384626:G:T	W38C	1.000
5:51384627:C:A	H39N	1.000
5:51384627:C:G	H39D	1.000
5:51384627:C:T	H39Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000119371 (5:51381875 A>G), RS1000170854 (5:51381473 A>G,T), RS1000803458 (5:51384435 G>A,T), RS1000865862 (5:51391563 C>A,T), RS1001058084 (5:51385333 T>A), RS1001425303 (5:51385773 C>A,T), RS1001866059 (5:51390190 G>A,T), RS1001897096 (5:51390072 AC>A), RS1002872530 (5:51389207 G>C), RS1003062099 (5:51383107 G>A,C), RS1003441672 (5:51383229 C>G,T), RS1004110993 (5:51393266 G>T), RS1004163890 (5:51384162 G>C), RS1004329905 (5:51390290 A>G), RS1005078982 (5:51386373 A>C,T)

Disease associations

OMIM: gene MIM:600366 | disease phenotypes: MIM:600057

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart disease	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Definitive	AD

Mondo (2): bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), congenital heart disease (MONDO:0005453)

Orphanet (1): Classic bladder exstrophy (Orphanet:93930)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000039	Epispadias
HP:0000056	Abnormal clitoris morphology
HP:0000069	Abnormality of the ureter
HP:0000076	Vesicoureteral reflux
HP:0001537	Umbilical hernia
HP:0001539	Omphalocele
HP:0002566	Intestinal malrotation
HP:0002607	Bowel incontinence
HP:0002836	Bladder exstrophy
HP:0004378	Abnormality of the anus
HP:0008736	Hypoplasia of penis

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001786_15	Dental caries	9.000000e-06
GCST002701_30	Verbal declarative memory	1.000000e-06
GCST002701_31	Verbal declarative memory	3.000000e-08
GCST002807_10	Classic bladder exstrophy	2.000000e-12
GCST003991_17	Childhood ear infection	3.000000e-07
GCST005171_42	QT interval	3.000000e-06
GCST006979_772	Heel bone mineral density	2.000000e-15
GCST007094_52	Diastolic blood pressure	2.000000e-08
GCST007099_213	Systolic blood pressure	9.000000e-07
GCST007323_77	Risk-taking tendency (4-domain principal component model)	1.000000e-10
GCST007325_268	General risk tolerance (MTAG)	9.000000e-14
GCST007327_64	Smoking status (ever vs never smokers)	4.000000e-08
GCST007329_17	Automobile speeding propensity	9.000000e-09
GCST007880_2	Emotional lability in attention deficit hyperactivity disorder	4.000000e-06
GCST008258_15	Alcohol use disorder (consumption score)	7.000000e-09
GCST008258_2	Alcohol use disorder (consumption score)	1.000000e-08
GCST009723_77	Vertical cup-disc ratio (adjusted for vertical disc diameter)	4.000000e-06
GCST009724_42	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-09
GCST010701_123	Cortical surface area (MOSTest)	7.000000e-11
GCST010702_110	Subcortical volume (MOSTest)	1.000000e-09
GCST010703_174	Brain morphology (MOSTest)	4.000000e-11
GCST010988_89	Adult body size	5.000000e-09
GCST90000047_100	Age at first sexual intercourse	7.000000e-09
GCST90002409_41	Childhood body mass index	3.000000e-06
GCST90014033_38	Haemorrhoidal disease	6.000000e-15

EFO canonical traits (16, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0004682	QT interval
EFO:0009270	heel bone mineral density
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008475	mood instability measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0004346	neuroimaging measurement
EFO:0009749	age at first sexual intercourse measurement
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Tretinoin	affects expression, decreases expression, increases expression	4
Benzo(a)pyrene	decreases methylation, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	affects cotreatment, increases methylation	1
methylmercuric chloride	increases expression	1
bisphenol A	increases methylation	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects methylation	1
butyraldehyde	increases expression	1
triacsin C	decreases expression	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
mercuric bromide	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
3-nitrobenzanthrone	affects expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
thifluzamide	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
XAV939	affects binding, affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(4-pyridyl)-1H-indole	affects cotreatment, increases expression	1
Pioglitazone	increases expression	1
Sunitinib	decreases expression	1

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_A3I3	SEES3-1V human ISL1, clone1	Embryonic stem cell	Male
CVCL_A3I4	SEES3-1V human ISL1, clone2	Embryonic stem cell	Male
CVCL_A3I5	SEES3-1V human ISL1, clone3	Embryonic stem cell	Male
CVCL_D6PC	WAe009-A-1G	Embryonic stem cell	Female
CVCL_ST10	HAP1 ISL1 (-) 1	Cancer cell line	Male
CVCL_XP86	HAP1 ISL1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function
NCT01827059	PHASE2	UNKNOWN	Bosentan In Exercise Induced Pulmonary Arterial Hypertension in CongenitaL Heart diseasE