Human Gene Module / Chromosome 7 / CUX1

CUX1cut like homeobox 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 14
Rare Variants / Common Variants
44 / 0
Aliases
CUX1, CASP,  CDP,  CDP/Cut,  CDP1,  COY1,  CUTL1,  CUX,  Clox,  Cux/CDP,  GOLIM6,  Nbla10317,  p100,  p110,  p200,  p75
Associated Syndromes
-
Chromosome Band
7q22.1
Associated Disorders
ID, ASD
Relevance to Autism

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. CUX1 was found to bind to a transcriptional activator containing an ASD-associated intronic haplotype in the EN2 gene (Choi et al., 2012).

Molecular Function

The protein encoded by this gene is a member of the homeodomain family of DNA binding proteins. It may regulate gene expression, morphogenesis, and differentiation and it may also play a role in the cell cycle progession.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CUX1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex Cubelos B , et al. (2010) No -
2 Support Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function Choi J , et al. (2011) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Primary Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
5 Support Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development Mitter D , et al. (2018) No ID, ASD
6 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
7 Support - Li D et al. (2022) Yes -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Suzuki T et al. (2022) No ASD, DD, ID
10 Support - Zhou X et al. (2022) Yes -
11 Support - Chan AJS et al. (2022) Yes -
12 Support - More RP et al. (2023) Yes -
13 Support - Yuan B et al. (2023) Yes -
14 Recent Recommendation - Oppermann H et al. (2023) No ASD, ADHD, epilepsy/seizures
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 30014507 Mitter D , et al. (2018)
- p.? inversion De novo - Simplex 37644171 Oppermann H et al. (2023)
c.63+1G>A - splice_site_variant Unknown - - 37644171 Oppermann H et al. (2023)
c.1943G>T p.Ser648Ile missense_variant Unknown - - 34968013 Li D et al. (2022)
c.4288G>T p.Glu1430Ter missense_variant De novo - - 36881370 Yuan B et al. (2023)
- - copy_number_loss Familial Maternal Simplex 37644171 Oppermann H et al. (2023)
c.61C>T p.Gln21Ter stop_gained De novo - Simplex 30014507 Mitter D , et al. (2018)
c.3161C>T p.Ser1054Leu missense_variant Unknown - - 35581205 Suzuki T et al. (2022)
c.3815G>A p.Arg1272Gln missense_variant Unknown - - 35581205 Suzuki T et al. (2022)
c.2617C>T p.Gln873Ter stop_gained De novo - Simplex 30014507 Mitter D , et al. (2018)
c.223-2A>G - splice_site_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.902T>C p.Val301Ala missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.571C>T p.Gln191Ter stop_gained De novo - Simplex 37644171 Oppermann H et al. (2023)
c.2839G>A p.Glu947Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
G>A - intergenic_variant Familial Both parents Simplex 27667684 Doan RN , et al. (2016)
c.1606C>T p.Gln536Ter stop_gained De novo - Simplex 37644171 Oppermann H et al. (2023)
c.1720C>T p.Gln574Ter stop_gained De novo - Simplex 37644171 Oppermann H et al. (2023)
c.3986C>G p.Ala1329Gly missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3596G>A p.Trp1199Ter stop_gained De novo - Simplex 37644171 Oppermann H et al. (2023)
G>A - intergenic_variant Familial Both parents Multiplex 27667684 Doan RN , et al. (2016)
c.3461del p.Asn1154ThrfsTer12 frameshift_variant De novo - - 36881370 Yuan B et al. (2023)
c.3281C>T p.Ala1094Val missense_variant Unknown - Simplex 35581205 Suzuki T et al. (2022)
c.4172C>T p.Thr1391Ile missense_variant Unknown - Simplex 35581205 Suzuki T et al. (2022)
c.1588A>C p.Lys530Gln missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.795G>C p.Arg265Ser missense_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.115G>A p.Glu39Lys missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.3634A>T p.Met1212Leu missense_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.4064C>T p.Thr1355Ile missense_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.3081C>T p.Pro1027%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.985G>T p.Glu329Ter stop_gained Familial Maternal Simplex 37644171 Oppermann H et al. (2023)
c.3783_3784dup p.Leu1262ArgfsTer10 frameshift_variant De novo - - 30014507 Mitter D , et al. (2018)
c.2398del p.Gln800ArgfsTer19 frameshift_variant De novo - Simplex 30014507 Mitter D , et al. (2018)
c.1609del p.Ser537AlafsTer39 frameshift_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.1626del p.Met543TrpfsTer33 frameshift_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.3334del p.Gln1112SerfsTer19 frameshift_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.3819del p.Tyr1274IlefsTer21 frameshift_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.1702del p.Ala568ProfsTer8 frameshift_variant Familial Paternal Simplex 36309498 Chan AJS et al. (2022)
c.4321dup p.Glu1441GlyfsTer121 frameshift_variant Unknown Not maternal - 37644171 Oppermann H et al. (2023)
c.4440_4448del p.Ser1482_Asp1484del frameshift_variant De novo - Simplex 37644171 Oppermann H et al. (2023)
c.3197dup p.Ala1067CysfsTer3 frameshift_variant Familial Maternal Multiplex 30014507 Mitter D , et al. (2018)
c.2902del p.Ala968ProfsTer35 frameshift_variant Familial Paternal Simplex 37644171 Oppermann H et al. (2023)
c.3533_3536del p.Arg1178ProfsTer9 frameshift_variant Familial Maternal Simplex 37644171 Oppermann H et al. (2023)
c.1091del p.Glu364GlyfsTer2 frameshift_variant Familial Paternal Extended multiplex 37644171 Oppermann H et al. (2023)
- p.Glu307_Glu1055delinsThrLeuGluAlaSerPheSerProAlaLysTrpAlaTer translocation De novo - Simplex 37644171 Oppermann H et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. Platzer et al., 2018 reported nine individuals harboring null-allele variants in the CUX1 gene that presented with developmental delay (primarily speech delay), motor delay, and intellectual disability.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We 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.

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. Platzer et al., 2018 reported nine individuals harboring null-allele variants in the CUX1 gene that presented with developmental delay (primarily speech delay), motor delay, and intellectual disability.

Reports Added
[New Scoring Scheme]
4/1/2019
2
icon
2

Score remained at 2

Description

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. Platzer et al., 2018 reported nine individuals harboring null-allele variants in the CUX1 gene that presented with developmental delay (primarily speech delay), motor delay, and intellectual disability.

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2018
2
icon
2

Score remained at 2

Description

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. Platzer et al., 2018 reported nine individuals harboring null-allele variants in the CUX1 gene that presented with developmental delay (primarily speech delay), motor delay, and intellectual disability.

Reports Added
[Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function.2011]
7/1/2018
3
icon
2

Decreased from 3 to 2

Description

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner. Platzer et al., 2018 reported nine individuals harboring null-allele variants in the CUX1 gene that presented with developmental delay (primarily speech delay), motor delay, and intellectual disability.

Reports Added
[Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development.2018]
10/1/2016
icon
3

Increased from to 3

Description

A rare G>A mutation within the human accelerated region HAR426, for which existing ChIA-Pet data showed an interaction with the dosage-sensitive CUX1 promoter 200 kb distal, was homozygous in three individuals presenting with ASD and ID from two unrelated consanguineous families; functional analysis of this variant in luciferase reporter assays demonstrated that while HAR426 joined to the human CUX1 promoter showed strong enhancer activity (1.5-fold increase), the G>A variant boosted activity over 3-fold (Doan et al., 2016). In the same report, overexpression of CUX1 in cortical cultured neurons was shown to increase synaptic spine density and spine head area in an activity-dependent manner.

Krishnan Probability Score

Score 0.49198153073878

Ranking 4853/25841 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.
Original Source
ExAC Score

Score 0.99998887753519

Ranking 465/18225 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
Original Source
Sanders TADA Score

Score 0.94890537013454

Ranking 17874/18665 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).
Original Source
Zhang D Score

Score -0.42867633751742

Ranking 18624/20870 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.
Original Source
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