EGR2
protein-codingearly growth response 2, the group of Zinc fingers C2H2-type
Gene summary
The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
- KROX20
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011890
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011527
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0015626
Submitter: ClinGen
EGR2, historically known as Krox-20, was first reported in relation to semidominant Charcot-Marie-Tooth Disease in 1998 (Warner et al., PMID: 9537424). The majority of known mutations show autosomal dominant inheritance, however at least two reported cases show autosomal recessive inheritance. More than 20 unique missense variants have been reported in the literature, mostly concentrated in the zinc finger domains. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in over 25 probands and over 10 publications (PMIDs: 9537424, 11523566, 17717711, 31852952, 26204789, 20513111, 32896048, 30481651, 27159987, 30843326). There is additionally a significant amount of segregation evidence, with a total summed LOD score of 5.62 over four families. The majority of these probands have adult-onset demyelinating forms of the disorder (labeled as CMT1D) with mild-moderate symptoms; however, early-onset forms with more severe symptoms (labeled as Dejerine-Sottas neuropathy or congenital hypomyelinating neuropathy) and axonal forms (labeled as CMT2) are also included in the general spectrum of this curation (PMIDs: 10371530, 26204789). More genetic evidence is available to review in the literature. The mechanism for disease varies by inheritance pattern. In the dominant form, missense variants in one of three zinc finger domains interfere with DNA binding and decrease the activity of wildtype DNM2 via inappropriate interactions with cofactors. The resulting severity is roughly correlated with the amount of residual DNA binding for a dominant negative effect. Recessive variants located in the R1 domain disallow the ability for the protein to bind and be repressed by NAB proteins, resulting in a loss of function and decreased amount of DNA binding (Warner et al. 1999, PMID: 10369870). This gene-disease relationship is also supported by several types of experimental evidence. Both a knock-in model harboring the recessive Ile268Asn variant and a hypomorphic model of the dominant forms both recapitulated the major phenotypes of the human disorder, including neuropathy, immature Schwann cells, severe hypomyelination, and cranial nerve involvement. Functional studies and protein interactions additionally demonstrate EGR2's importance to myelination, with MPZ activation and expression severely affected by mutant co-expression. In summary, EGR2 is DEFINITIVELY associated with semidominant Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: SD
Disease ID:MONDO:0007790
Submitter: Ambry Genetics
Inheritance Pattern: SD
Disease ID:MONDO:0015626
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007790
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011527
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011890
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011527
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0011527
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011890
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EGR2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000399.5. 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 | 1 | 125 | 126 | |||
| missense | 10 | 16 | 240 | 8 | 274 | |
| nonsense | 4 | 4 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 7 | 7 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 10 | 16 | 253 | 133 | 0 | 412 |
Highest pathogenic variant AF is 6.8443086e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000390.2 | 2 | MANE Select | |
| Ensembl | ENSP00000242480.3 | 2 | MANE Select | |
| RefSeq | NP_001129649.1 | 2 | Standard | |
| RefSeq | NP_001129650.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| egr2b | Danio rerio | Structure: posterior lateral line nerve Quality: absent abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- HTLV-I infection - Homo sapiens (human)
- C-type lectin receptor signaling pathway - Homo sapiens (human)
- Viral carcinogenesis - Homo sapiens (human)
- Hepatitis B - Homo sapiens (human)
- White fat cell differentiation
Biological Process
- regulation of transcription by RNA polymerase II
- transcription by RNA polymerase II
- protein export from nucleus
- brain development
- peripheral nervous system development
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
- DNA-binding transcription activator activity, RNA polymerase II-specific
- chromatin binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- intracellular membrane-bounded organelle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000242480
- Coding exons
- 2
- Length
- 107905
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125748
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.44 | 175 | 293 | 0.598 | 0.0000187 | 3049 |
| Missense (PolyPhen) | 28 | 62.834 | 0.44562 | 668 | ||
| Synonymous | -0.584 | 131 | 123 | 1.07 | 0.00000797 | 1085 |
| Loss of Function | 2.42 | 2 | 10.4 | 0.192 | 6.37e-7 | 122 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Sequence-specific DNA-binding transcription factor. Binds to two specific DNA sites located in the promoter region of HOXA4. {ECO:0000269|PubMed:21836637}.;
- Disease
- DISEASE: Neuropathy, congenital hypomyelinating or amyelinating (CHN) [MIM:605253]: A severe degenerating neuropathy that results from a congenital impairment in myelin formation. It is clinically characterized by early onset of hypotonia, areflexia, distal muscle weakness, and very slow nerve conduction velocities (as low as 3m/s). Some patients manifest nearly complete absence of spontaneous limb movements, respiratory distress at birth, and complete absence of myelin shown by electron microscopy of peripheral nerves. Inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:22522483, ECO:0000269|PubMed:9537424}. Note=The disease is caused by mutations affecting the gene represented in this entry. Patients affected by the amyelinating form carry a causative, homozygous deletion encompassing a myelin-specific enhancer of EGR2 (PubMed:22522483). {ECO:0000269|PubMed:22522483}.; DISEASE: Charcot-Marie-Tooth disease 1D (CMT1D) [MIM:607678]: A dominant demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. {ECO:0000269|PubMed:10502832, ECO:0000269|PubMed:10762521, ECO:0000269|PubMed:11239949, ECO:0000269|PubMed:12736090, ECO:0000269|PubMed:15241803, ECO:0000269|PubMed:15947997, ECO:0000269|PubMed:9537424, ECO:0000269|Ref.15}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dejerine-Sottas syndrome (DSS) [MIM:145900]: A severe degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. Characterized by motor and sensory neuropathy with very slow nerve conduction velocities, increased cerebrospinal fluid protein concentrations, hypertrophic nerve changes, delayed age of walking as well as areflexia. There are both autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome. {ECO:0000269|PubMed:10371530}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.665
Intolerance Scores
- LoFtool
- 0.233
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 37.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.996
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |