DGCR8: A Key Regulator of microRNA Biogenesis
DGCR8 (DGCR8 Microprocessor Complex Subunit) is a critical component of the microprocessor complex, essential for the initial processing of primary microRNA transcripts.
Gene Information Card
| Symbol | DGCR8 |
|---|---|
| Full Name | DGCR8 Microprocessor Complex Subunit |
| Gene Type | Protein-coding |
| Chromosomal Location | 22q11.21 |
| NCBI Gene ID | 54487 ncbi.nlm.nih.gov/gene/54487 |
| Ensembl ID | ENSG00000128191 |
| UniProt ID | Q8WYQ5 |
| OMIM ID | 609030 |
| HGNC ID | 2847 |
| Aliases | C22orf12, DGCRK6, pasha, microprocessor complex subunit DGCR8 |
Description
DGCR8 (DGCR8 Microprocessor Complex Subunit) encodes a protein that is a core component of the microprocessor complex, which also includes DROSHA. This complex is responsible for cleaving primary microRNA (pri-miRNA) transcripts into precursor microRNA (pre-miRNA) hairpins, a critical step in the microRNA biogenesis pathway. The DGCR8 protein contains a double-stranded RNA-binding domain (dsRBD) that recognizes pri-miRNA substrates and a heme-binding domain that regulates its activity. DGCR8 is essential for proper microRNA maturation and subsequent gene regulation. Haploinsufficiency of DGCR8, often due to 22q11.2 deletion, is associated with DiGeorge syndrome and increased risk for schizophrenia and other neurodevelopmental disorders. Altered DGCR8 expression is also implicated in various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| DiGeorge Syndrome (22q11.2 Deletion Syndrome) | Haploinsufficiency of DGCR8 due to 22q11.2 deletion disrupts microRNA processing, leading to altered gene expression in developing neural crest cells and thymus. | OMIM #188400; NCBI Gene; ClinVar |
| Schizophrenia | Reduced DGCR8 expression impairs microRNA biogenesis, affecting synaptic plasticity and neuronal development, increasing risk. | OMIM #181500; PubMed studies; ClinVar |
| Breast Cancer | DGCR8 overexpression or amplification leads to global upregulation of microRNAs, promoting tumorigenesis and metastasis. | COSMIC; PubMed studies |
| Wilms Tumor | Somatic mutations and altered expression of DGCR8 contribute to disrupted microRNA processing in nephroblastoma. | COSMIC; PubMed studies |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 15.2 | High |
| Testis | 12.8 | High |
| Thyroid | 10.5 | Medium |
| Lung | 8.3 | Medium |
| Liver | 6.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 18.4 | Embryonic kidney cells; high expression |
| HeLa | 14.7 | Cervical cancer cells; moderate-high |
| MCF7 | 12.1 | Breast cancer cells; moderate |
| SH-SY5Y | 16.3 | Neuroblastoma cells; high expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1390C>T (p.Arg464Trp) | Missense | Rare | Reduced RNA-binding affinity and microprocessor activity; associated with DiGeorge syndrome-like phenotypes. |
| c.1688G>A (p.Arg563Gln) | Missense | Rare | Impaired heme binding and decreased pri-miRNA processing efficiency. |
| c.1129_1130insC (p.Gln377ProfsTer12) | Frameshift | Rare | Loss-of-function; truncation of protein, leading to haploinsufficiency. |
| Amplification (22q11.21 gain) | Copy number gain | Common in breast cancer | Increased DGCR8 expression and global microRNA upregulation. |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations (e.g., c.1129_1130insC) that truncate the protein or disrupt the dsRBD or heme-binding domain lead to reduced microprocessor activity and impaired microRNA biogenesis.
Gain of Function (GOF)
Amplification or overexpression of DGCR8 (e.g., in breast cancer) results in increased processing of pri-miRNAs, leading to global microRNA upregulation and oncogenic effects.
Dominant Negative (DN)
Missense mutations (e.g., p.Arg464Trp) that retain partial function but disrupt complex assembly or substrate recognition can act in a dominant-negative manner, reducing overall microprocessor activity.
View complete mutation data：
Gene Ontology (GO)
Pathways
• MicroRNA biogenesis (R-HSA-2032785)
• Gene silencing by RNA (R-HSA-74160)
• DiGeorge syndrome pathway (WP4200)
Protein Summary
The DGCR8 protein (also known as Pasha) is a 773-amino acid nuclear protein that forms the microprocessor complex with DROSHA. It contains two double-stranded RNA-binding domains (dsRBD1 and dsRBD2) that recognize and bind pri-miRNA substrates, and a C-terminal heme-binding domain that stabilizes the protein and regulates its activity. DGCR8 acts as a molecular ruler, measuring the distance from the pri-miRNA stem-loop to the cleavage site, ensuring precise processing by DROSHA. The protein is essential for the production of most canonical microRNAs and thus influences a wide range of cellular processes including development, differentiation, and proliferation.
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