DPP6dipeptidyl-peptidase 6
Autism Reports / Total Reports
13 / 28Rare Variants / Common Variants
24 / 1Aliases
DPP6, DPPX, MGC46605Associated Syndromes
-Chromosome Band
7q36.2Associated Disorders
ADHDRelevance to Autism
Rare mutations in the DPP6 gene have been identified with autism (Marshall et al., 2008; ORoak et al., 2012). In addition, genetic association has been found between DPP6 and amyotrophic lateral sclerosis (ALS) (van Es et al., 2008).
Molecular Function
This protein modulates the kinetics of transient A-type currents.
External Links
SFARI Genomic Platforms
Reports related to DPP6 (28 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Recent Recommendation | Species and tissue differences in the expression of DPPY splicing variants | Takimoto K , et al. (2006) | No | - |
| 2 | Recent Recommendation | Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis | van Es MA , et al. (2007) | No | - |
| 3 | Primary | Structural variation of chromosomes in autism spectrum disorder | Marshall CR , et al. (2008) | Yes | - |
| 4 | Recent Recommendation | Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons | Amarillo Y , et al. (2008) | No | - |
| 5 | Recent Recommendation | I SA channel complexes include four subunits each of DPP6 and Kv4.2 | Soh H and Goldstein SA (2008) | No | - |
| 6 | Recent Recommendation | Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels | Radicke S , et al. (2008) | No | - |
| 7 | Recent Recommendation | Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons | Kim J , et al. (2008) | No | - |
| 8 | Recent Recommendation | DPP6 Localization in Brain Supports Function as a Kv4 Channel Associated Protein | Clark BD , et al. (2008) | No | - |
| 9 | Recent Recommendation | A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis | Chi A , et al. (2009) | No | - |
| 10 | Recent Recommendation | The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels | Kaulin YA , et al. (2009) | No | - |
| 11 | Recent Recommendation | The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels | Dougherty K , et al. (2009) | No | - |
| 12 | Recent Recommendation | Augmentation of Kv4.2-encoded currents by accessory dipeptidyl peptidase 6 and 10 subunits reflects selective cell surface Kv4.2 protein stabilization | Foeger NC , et al. (2012) | No | - |
| 13 | Support | Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations | O'Roak BJ , et al. (2012) | Yes | - |
| 14 | Support | A discovery resource of rare copy number variations in individuals with autism spectrum disorder | Prasad A , et al. (2013) | Yes | - |
| 15 | Support | Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder | Girirajan S , et al. (2013) | Yes | - |
| 16 | Recent Recommendation | Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation | Liao C , et al. (2013) | No | - |
| 17 | Recent Recommendation | DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development | Lin L , et al. (2013) | No | - |
| 18 | Support | Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families | Egger G , et al. (2014) | Yes | - |
| 19 | Support | DPP6 gene disruption in a family with Gilles de la Tourette syndrome | Prontera P , et al. (2014) | No | ADHD |
| 20 | Support | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 21 | Support | Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder | Tammimies K , et al. (2015) | Yes | - |
| 22 | Support | Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance | Bock I , et al. (2016) | Yes | - |
| 23 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 24 | Support | Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes | Feliciano P et al. (2019) | Yes | - |
| 25 | Support | - | Hu C et al. (2022) | Yes | - |
| 26 | Support | - | Zhou X et al. (2022) | Yes | - |
| 27 | Support | - | Hu C et al. (2023) | Yes | - |
| 28 | Highly Cited | Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression | Hough RB , et al. (1998) | No | - |
Rare Variants (24)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | copy_number_loss | De novo | - | - | 23832105 | Liao C , et al. (2013) | |
| - | - | copy_number_loss | Unknown | - | - | 24643514 | Egger G , et al. (2014) | |
| - | - | copy_number_loss | De novo | - | - | 26325558 | Tammimies K , et al. (2015) | |
| - | - | copy_number_loss | Unknown | - | Unknown | 23275889 | Prasad A , et al. (2013) | |
| - | - | copy_number_gain | Unknown | - | Simplex | 18252227 | Marshall CR , et al. (2008) | |
| - | - | copy_number_loss | De novo | - | Simplex | 18252227 | Marshall CR , et al. (2008) | |
| c.958A>G | p.Thr320Ala | missense_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.661C>T | p.Gln221Ter | stop_gained | De novo | - | - | 31452935 | Feliciano P et al. (2019) | |
| - | - | copy_number_gain | Familial | Paternal | Multiplex | 24643514 | Egger G , et al. (2014) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 22495309 | O'Roak BJ , et al. (2012) | |
| - | - | copy_number_gain | Familial | Maternal | Simplex | 18252227 | Marshall CR , et al. (2008) | |
| - | - | copy_number_gain | Familial | Maternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_gain | Familial | Paternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_loss | Familial | Maternal | Simplex | 23375656 | Girirajan S , et al. (2013) | |
| - | - | copy_number_gain | Familial | Maternal | Multiplex | 18252227 | Marshall CR , et al. (2008) | |
| - | - | copy_number_gain | Familial | Maternal | Multiplex | 23375656 | Girirajan S , et al. (2013) | |
| c.779C>G | p.Pro260Arg | missense_variant | Familial | Maternal | - | 37007974 | Hu C et al. (2023) | |
| c.1511C>T | p.Thr504Ile | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.940G>A | p.Ala314Thr | missense_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| - | - | copy_number_loss | Familial | Paternal | Extended multiplex | 25129042 | Prontera P , et al. (2014) | |
| c.45_51+3del | - | splice_site_variant | Familial | Paternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.1337_1337+3del | - | splice_site_variant | Familial | Paternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.964C>T | p.Arg322Cys | missense_variant | Familial | Paternal | Multi-generational | 27651234 | Bock I , et al. (2016) | |
| c.1153A>C | p.Met385Leu | missense_variant | Familial | Maternal and Paternal | Multi-generational | 23832105 | Liao C , et al. (2013) |
Common Variants (1)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.266-26819T>C;c.272-26819T>C;c.458-26819T>C;c.275-26819T>C | - | intron_variant | - | - | - | 18084291 | van Es MA , et al. (2007) |
SFARI Gene score
2
Strong Candidate
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
4/1/2022
3
2
Decreased from 3 to 2
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
7/1/2019
4
4
Decreased from 4 to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
10/1/2016
4
4
Decreased from 4 to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
1/1/2016
4
4
Decreased from 4 to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
Reports Added
[Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.2007] [Structural variation of chromosomes in autism spectrum disorder.2008] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation.2013] [DPP6 gene disruption in a family with Gilles de la Tourette syndrome.2014] [Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression.1998] [Species and tissue differences in the expression of DPPY splicing variants.2006] [Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K channels in cerebellar granule neurons.2008] [I SA channel complexes include four subunits each of DPP6 and Kv4.2.2008] [Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels.2008] [Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.2008] [DPP6 Localization in Brain Supports Function as a Kv4 Channel Associated Protein.2008] [A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.2009] [The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels.2009] [The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.2009] [Augmentation of Kv4.2-encoded currents by accessory dipeptidyl peptidase 6 and 10 subunits reflects selective cell surface Kv4.2 protein stabilizat...2012] [DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development.2013] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]7/1/2015
4
4
Decreased from 4 to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
Reports Added
[Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.2007] [Structural variation of chromosomes in autism spectrum disorder.2008] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation.2013] [DPP6 gene disruption in a family with Gilles de la Tourette syndrome.2014] [Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression.1998] [Species and tissue differences in the expression of DPPY splicing variants.2006] [Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K channels in cerebellar granule neurons.2008] [I SA channel complexes include four subunits each of DPP6 and Kv4.2.2008] [Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels.2008] [Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.2008] [DPP6 Localization in Brain Supports Function as a Kv4 Channel Associated Protein.2008] [A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.2009] [The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels.2009] [The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.2009] [Augmentation of Kv4.2-encoded currents by accessory dipeptidyl peptidase 6 and 10 subunits reflects selective cell surface Kv4.2 protein stabilizat...2012] [DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development.2013] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015]7/1/2014
No data
4
Increased from No data to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
Reports Added
[Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression.1998] [Species and tissue differences in the expression of DPPY splicing variants.2006] [Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.2007] [Structural variation of chromosomes in autism spectrum disorder.2008] [Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K channels in cerebellar granule neurons.2008] [I SA channel complexes include four subunits each of DPP6 and Kv4.2.2008] [Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels.2008] [Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.2008] [DPP6 Localization in Brain Supports Function as a Kv4 Channel Associated Protein.2008] [A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.2009] [The dipeptidyl-peptidase-like protein DPP6 determines the unitary conductance of neuronal Kv4.2 channels.2009] [The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.2009] [Augmentation of Kv4.2-encoded currents by accessory dipeptidyl peptidase 6 and 10 subunits reflects selective cell surface Kv4.2 protein stabilizat...2012] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation.2013] [DPP6 regulation of dendritic morphogenesis impacts hippocampal synaptic development.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [DPP6 gene disruption in a family with Gilles de la Tourette syndrome.2014]4/1/2014
No data
4
Increased from No data to 4
Description
Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).
Krishnan Probability Score
Score 0.76556798240313
Ranking 12/25841 scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
ExAC Score
Score 0.96769110706309
Ranking 2409/18225 scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score
Score 0.35516167774394
Ranking 228/18665 scored genes
[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score
Score 0.27053145635811
Ranking 3181/20870 scored genes
[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| PRNP | Prion protein | Mouse | Protein Binding | 19122 | P04925 |