DPP6: Dipeptidyl Peptidase 6 - A Key Regulator of Neuronal Excitability
Comprehensive genomic and functional analysis of DPP6, a potassium channel auxiliary subunit implicated in neurological disorders and cancer.
Gene Information Card
| Symbol | DPP6 |
|---|---|
| Full Name | Dipeptidyl Peptidase 6 |
| Gene Type | Protein coding |
| Chromosomal Location | 7q36.2 |
| NCBI Gene ID | 1807 ncbi.nlm.nih.gov/gene/1807 |
| Ensembl ID | ENSG00000106331 |
| UniProt ID | P42658 |
| OMIM ID | 126141 |
| HGNC ID | 3010 |
| Aliases | DPPX, DPPX, VF2, DPL1 |
Description
DPP6 (Dipeptidyl Peptidase 6) encodes a member of the S9B serine protease family, but the protein lacks detectable peptidase activity. It functions as an auxiliary subunit of voltage-gated potassium channels (Kv4 family), modulating channel gating, surface expression, and neuronal excitability. DPP6 is highly expressed in the brain, particularly in the hippocampus, cerebellum, and cortex. Mutations and altered expression are linked to intellectual disability, epilepsy, amyotrophic lateral sclerosis (ALS), and various cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Intellectual disability (autosomal dominant) | Missense mutations in DPP6 impair Kv4 channel modulation, leading to altered neuronal firing and synaptic plasticity. | ClinVar, OMIM #126141 |
| Epilepsy (focal, with variable phenotypes) | Loss-of-function variants reduce potassium current density, increasing neuronal hyperexcitability. | ClinVar, PubMed studies |
| Amyotrophic lateral sclerosis (ALS) | DPP6 expression is altered in spinal motor neurons; genetic variants may contribute to susceptibility. | NCBI Gene, PubMed |
| Colorectal cancer | DPP6 overexpression promotes tumor cell proliferation and migration via modulation of Kv4 channels. | COSMIC, PubMed |
| Breast cancer | DPP6 upregulation correlates with poor prognosis; may influence cell cycle progression. | COSMIC, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | 38.2 | High |
| Brain (hippocampus) | 45.1 | High |
| Brain (cerebellum) | 52.3 | High |
| Testis | 6.8 | Low |
| Pancreas | 4.2 | Low |
| Liver | 1.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 12.5 | Neuronal model |
| U-87 MG (glioblastoma) | 8.3 | Glial tumor |
| HEK293 (embryonic kidney) | 0.9 | Low expression |
| MCF7 (breast cancer) | 6.7 | Hormone-responsive |
| HCT116 (colorectal cancer) | 15.4 | High expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1015G>A (p.Gly339Arg) | Missense | Rare | Impaired Kv4.2 modulation; associated with intellectual disability |
| c.1246C>T (p.Arg416Trp) | Missense | Rare | Reduced channel surface expression; linked to epilepsy |
| c.1573_1575del (p.Phe525del) | In-frame deletion | Rare | Altered gating kinetics; reported in ALS |
| c.2002C>T (p.Arg668*) | Nonsense | Very rare | Premature truncation; loss of function |
| c.788A>G (p.Asn263Ser) | Missense | Somatic (COSMIC) | Unknown functional effect; found in colorectal cancer |
Mutation functional classification
Loss of Function (LOF)
Missense and nonsense variants that reduce Kv4 channel modulation or surface expression, leading to neuronal hyperexcitability (e.g., p.Arg416Trp, p.Arg668*).
Gain of Function (GOF)
Not well documented; some somatic mutations in cancer may enhance channel activity, but evidence is limited.
Dominant Negative (DN)
Heterozygous missense mutations (e.g., p.Gly339Arg) that disrupt wild-type DPP6 function in Kv4 channel complexes, consistent with autosomal dominant inheritance.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Kv4-mediated potassium channel regulation (Reactome: R-HSA-1296071)
• Neuronal system (Reactome: R-HSA-112316)
• Transmission across chemical synapses (Reactome: R-HSA-112315)
Protein Summary
DPP6 (also known as DPPX) is a 865-amino acid type II transmembrane glycoprotein belonging to the dipeptidyl peptidase IV family. Despite its structural homology to serine proteases, it lacks catalytic activity due to critical active site mutations. DPP6 functions as an auxiliary subunit of A-type voltage-gated potassium channels (Kv4.2 and Kv4.3), accelerating channel inactivation and increasing surface expression. It is predominantly expressed in the brain, where it regulates dendritic excitability, backpropagation of action potentials, and synaptic plasticity. Alternative splicing generates multiple isoforms with distinct tissue distributions and functional properties.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| DPP6 Knockout HEK293 Cell Line | EDJ-KQ4472 | Human | 1804 | Details Get a Quote |
| DPP6 Knockout HeLa Cell Line | EDJ-KQ53109 | Human | 1804 | Details Get a Quote |
| DPP6 Knockout A-549 Cell Line | EDJ-KQ61582 | Human | 1804 | Details Get a Quote |
| DPP6 Knockout HCT 116 Cell Line | EDJ-KQ70072 | Human | 1804 | Details Get a Quote |
