Human Gene Module / Chromosome 7 / DPP6

DPP6dipeptidyl-peptidase 6

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
9 / 24
Rare Variants / Common Variants
20 / 1
Aliases
DPP6, DPPX,  MGC46605
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Chromosome Band
7q36.2
Associated Disorders
ADHD
Relevance 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.

Reports related to DPP6 (24 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 stabilizat... 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... 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 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   (20)
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)
- - 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)
delGTAA - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.940G>A p.Ala314Thr missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
- - copy_number_loss Familial Paternal Multi-generational 25129042 Prontera P , et al. (2014)
delGTGATGGTGA - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
- - copy_number_gain Familial Paternal Possibly multi-generational 24643514 Egger G , et al. (2014)
c.964C>T p.Arg322Cys missense_variant Familial Paternal Possibly multi-generational 27651234 Bock I , et al. (2016)
c.1153A>C p.Met385Leu missense_variant Familial Maternal & 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
3

Suggestive Evidence

Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2019
4
icon
4

Score remained at 4

Description

Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).

10/1/2016
4
icon
4

Score remained at 4

Description

Found in an ASD-associated CNV without independent replication (Marshall et al., 2008).

1/1/2016
4
icon
4

Score remained at 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 disorder.2014]
7/1/2015
4
icon
4

Score remained at 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
icon
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
icon
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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
PRNP Prion protein Mouse Protein Binding 19122 P04925
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