HERC2 Gene: E3 Ubiquitin-Protein Ligase and Pigmentation Regulator
Comprehensive genomic and clinical overview of HERC2, a key regulator of melanocyte function and neurodevelopment.
Gene Information Card
| Symbol | HERC2 |
|---|---|
| Full Name | HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 15q13.1 |
| NCBI Gene ID | 8927 ncbi.nlm.nih.gov/gene/8927 |
| Ensembl ID | ENSG00000128731 |
| UniProt ID | O95714 |
| OMIM ID | 605837 |
| HGNC ID | 4868 |
| Aliases | HECTH2, p528, D15F37S1, SHEP1 |
Description
HERC2 encodes a large E3 ubiquitin-protein ligase belonging to the HERC family. The protein contains a HECT domain and RCC1-like domains (RLDs), mediating ubiquitination of target proteins involved in DNA repair, cell cycle regulation, and melanogenesis. HERC2 is critical for pigmentation through its interaction with OCA2, and mutations are linked to neurodevelopmental disorders including Angelman-like syndrome and Prader-Willi-like phenotypes. The gene is also associated with blue/brown eye color variation via an intronic SNP (rs12913832) that regulates OCA2 expression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Angelman syndrome-like (AS-L) | Loss-of-function mutations in HERC2 impair ubiquitination of UBE3A, leading to reduced UBE3A activity and neurodevelopmental deficits. | ClinVar, OMIM #605837 |
| Prader-Willi-like syndrome | Deletions or mutations in 15q13.1 encompassing HERC2 disrupt hypothalamic function and melanocortin signaling. | OMIM #176270, NCBI |
| Autism spectrum disorder (ASD) | Rare HERC2 variants identified in ASD cohorts; altered synaptic ubiquitination may contribute to neuronal dysfunction. | ClinVar, PubMed |
| Oculocutaneous albinism type 2 (OCA2) modifier | HERC2 intronic SNP rs12913832 regulates OCA2 promoter activity, influencing melanin production and eye color. | OMIM #203200, NCBI |
| Intellectual disability | Homozygous HERC2 missense mutations (e.g., p.Arg1053Gln) cause syndromic intellectual disability with speech delay. | ClinVar, OMIM #605837 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Testis | 8.2 | Low |
| Skin | 6.7 | Low |
| Lung | 4.1 | Not detected |
| Liver | 3.8 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 10.1 | Moderate expression |
| SH-SY5Y | 9.5 | Neuronal cell line |
| A375 (melanoma) | 7.8 | Melanocyte-derived |
| HeLa | 6.2 | Low expression |
| K562 | 4.5 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs12913832 (intronic) | SNP | Common (40-80% in Europeans) | Regulates OCA2 expression; associated with blue/brown eye color |
| c.3157C>T (p.Arg1053Gln) | Missense | Rare | Loss of function; causes intellectual disability and Angelman-like syndrome |
| c.1786C>T (p.Arg596*) | Nonsense | Rare | Premature truncation; loss of E3 ligase activity |
| 15q13.1 microdeletion | Copy number loss | 0.5-1% in neurodevelopmental cohorts | Haploinsufficiency; Prader-Willi-like phenotype |
| c.4825G>A (p.Gly1609Arg) | Missense | Rare | Impaired HECT domain; reduced ubiquitination |
Mutation functional classification
Loss of Function (LOF)
Nonsense and missense mutations in the HECT domain (e.g., p.Arg596*, p.Arg1053Gln) abolish E3 ubiquitin ligase activity, leading to reduced UBE3A ubiquitination and neurodevelopmental disorders.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in HERC2; all pathogenic variants are loss-of-function or regulatory.
Dominant Negative (DN)
Heterozygous missense mutations in the RLD domain may interfere with wild-type HERC2 function, but dominant-negative effects are not well established.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Ubiquitin mediated proteolysis (KEGG: hsa04120)
• p53 signaling pathway (KEGG: hsa04115) - HERC2 ubiquitinates MDM2
• Melanogenesis (KEGG: hsa04916) - via OCA2 regulation
• DNA damage response (Reactome: R-HSA-73893)
Protein Summary
HERC2 is a 4834-amino acid E3 ubiquitin-protein ligase with a C-terminal HECT domain and three N-terminal RCC1-like domains (RLDs). It ubiquitinates key substrates including UBE3A, MDM2, and XPA, thereby regulating DNA repair, cell cycle, and pigmentation. The protein localizes to the nucleus and cytoplasm, and its expression is highest in brain and testis. HERC2 dysfunction underlies multiple neurodevelopmental and pigmentation disorders.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HERC2 Knockout HEK293 Cell Line | EDJ-KQ2447 | Human | 8924 | Details Get a Quote |
| HERC2 Knockout A-549 Cell Line | EDJ-KQ22968 | Human | 8924 | Details Get a Quote |
| HERC2 Knockout HCT 116 Cell Line | EDJ-KQ22969 | Human | 8924 | Details Get a Quote |
| HERC2 Knockout HeLa Cell Line | EDJ-KQ22970 | Human | 8924 | Details Get a Quote |
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