ISL1
protein-codingISL LIM homeobox 1, the group of LIM class homeoboxes
Gene summary
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. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005453
Submitter: ClinGen
*ISL1* was first reported in relation to autosomal dominant congenital heart disease in 2014 (Osoegawa et al., PMID: 25077177). Five unique variants (nonsense, gross deletion, promoter) that have been reported in five individuals with CHD are included in this curation (PMID: 25077177, 30390123, 31484864, 32820510, 34260301). The mechanism of pathogenicity is predicted to be loss-of-function. This gene-disease relationship is also supported by evidence of *ISL1* expression in both the human and murine fetal heart, biochemical function studies showing the role of *Isl1/Brg1-Baf60c* complex in cardiogenesis, and two mouse models (knockout and hypomorphic) showing severe developmental defects of the mutant heart (PMIDs: 19571884, 14667410, 31024170). In summary, *ISL1* is definitively associated with autosomal dominant congenital heart disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 6th, 2024 (SOP Version 10).
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ISL1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002202.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 59 | 3 | 62 | |||
| missense | 77 | 1 | 78 | |||
| nonsense | 0 | |||||
| start loss | 1 | 1 | ||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 79 | 60 | 3 | 142 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002193.2 | 6 | MANE Select | |
| Ensembl | ENSP00000230658.7 | 6 | MANE Select | |
| Ensembl | ENSP00000422676.1 | 6 | Standard | |
| Ensembl | ENSP00000637765.1 | 4 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| isl1 | Danio rerio | Structure: secondary motor neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
- Heart Development
- Neural Crest Differentiation
- Cardiac Progenitor Differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- neural crest cell migration
- secondary heart field specification
- outflow tract septum morphogenesis
- outflow tract morphogenesis
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II activating transcription factor binding
- enhancer sequence-specific DNA binding
- DNA-binding transcription activator activity, RNA polymerase II-specific
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000230658
- Coding exons
- 6
- Length
- 11644
- Individuals with no LoFs
- 124752
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124754
- p
- 0.00000802
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.87 | 124 | 198 | 0.625 | 0.00000922 | 2310 |
| Missense (PolyPhen) | 17 | 63.045 | 0.26965 | 750 | ||
| Synonymous | -1.47 | 89 | 73.0 | 1.22 | 0.00000361 | 656 |
| Loss of Function | 3.17 | 2 | 15.4 | 0.130 | 6.65e-7 | 179 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000065 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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 (By similarity). {ECO:0000250|UniProtKB:P61372, ECO:0000250|UniProtKB:P61374}.;
Intolerance Scores
- LoFtool
- 0.179
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 28.63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.987
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |