Human Gene Module / Chromosome 10 / UPF2

UPF2UPF2, regulator of nonsense mediated mRNA decay

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 10
Rare Variants / Common Variants
13 / 0
Aliases
UPF2, HUPF2,  RENT2,  smg-3
Associated Syndromes
-
Chromosome Band
10p14
Associated Disorders
ASD
Relevance to Autism

CNVs involving UPF2 were statistically enriched in a cohort of 57.356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Molecular Function

This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to UPF2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders Nguyen LS , et al. (2013) No ASD
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation A common molecular signature in ASD gene expression: following Root 66 to autism Diaz-Beltran L , et al. (2016) No -
4 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No -
5 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
7 Recent Recommendation Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response Johnson JL , et al. (2019) No ASD
8 Support UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function Notaras M , et al. (2019) No -
9 Support - Hildebrand MS et al. (2020) No -
10 Support - Zhou X et al. (2022) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 31585809 Johnson JL , et al. (2019)
- - copy_number_loss De novo - Unknown 23376982 Nguyen LS , et al. (2013)
c.-15G>T - missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.3517A>T p.Met1173Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2289C>T p.Thr763%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3035-3A>C - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1095dup p.His366ThrfsTer13 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.986del p.Ser329MetfsTer8 frameshift_variant De novo - - 31585809 Johnson JL , et al. (2019)
c.1940del p.Asp647ValfsTer24 frameshift_variant De novo - - 31585809 Johnson JL , et al. (2019)
c.1958G>A p.Arg653Gln missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
AC>A - frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1940del p.Asp647ValfsTer24 frameshift_variant De novo - Simplex 32345733 Hildebrand MS et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013). Johnson et al., 2019 identified three unrelated individuals with novel de novo UPF2 variants (two individuals with frameshift variants that presented with speech and language disorders, and a third individual with a deletion that presented with ASD and intellectual disability); functional analysis of patient-derived lymphoblastoid cell lines demonstrated decreased UPF2 mRNA and protein levels, as well as impaired nonsense-mediated decay (NMD). Furthermore, in the same report, Upf2-deficient mice were shown to exhibit impaired NMD, synaptic plasticity deficits, deficits in social behavior, impaired behavioral flexibility, and increased immune activation.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013). Johnson et al., 2019 identified three unrelated individuals with novel de novo UPF2 variants (two individuals with frameshift variants that presented with speech and language disorders, and a third individual with a deletion that presented with ASD and intellectual disability); functional analysis of patient-derived lymphoblastoid cell lines demonstrated decreased UPF2 mRNA and protein levels, as well as impaired nonsense-mediated decay (NMD). Furthermore, in the same report, Upf2-deficient mice were shown to exhibit impaired NMD, synaptic plasticity deficits, deficits in social behavior, impaired behavioral flexibility, and increased immune activation.

10/1/2019
5
icon
3

Decreased from 5 to 3

New Scoring Scheme
Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013). Johnson et al., 2019 identified three unrelated individuals with novel de novo UPF2 variants (two individuals with frameshift variants that presented with speech and language disorders, and a third individual with a deletion that presented with ASD and intellectual disability); functional analysis of patient-derived lymphoblastoid cell lines demonstrated decreased UPF2 mRNA and protein levels, as well as impaired nonsense-mediated decay (NMD). Furthermore, in the same report, Upf2-deficient mice were shown to exhibit impaired NMD, synaptic plasticity deficits, deficits in social behavior, impaired behavioral flexibility, and increased immune activation.

Reports Added
[Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response.2019] [UPF2 leads to degradation of dendritically targeted mRNAs to regulate synaptic plasticity and cognitive function.2019] [New Scoring Scheme]
4/1/2019
5
icon
5

Decreased from 5 to 5

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2018
5
icon
5

Decreased from 5 to 5

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2016
5
icon
5

Decreased from 5 to 5

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Reports Added
[The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
1/1/2016
5
icon
5

Decreased from 5 to 5

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Reports Added
[Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders.2013] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A common molecular signature in ASD gene expression: following Root 66 to autism.2016]
7/1/2015
icon
5

Increased from to 5

Description

CNVs involving UPF2 were statistically enriched in a cohort of 57,356 patients with neurodevelopmental disorders compared to a cohort of 20,474 controls (deletions, P=0.034805; duplications, P=0.018903). A de novo 2.04 Mb deletion encompassing the UPF2 gene was detected in a female patient from the Developmental Gene Discovery Project (DGDP151) with autism spectrum disorder, intellectual disability, trichotillomania, aggressive behavior, and neuroregression (Nguyen et al., 2013).

Krishnan Probability Score

Score 0.49501013914832

Ranking 3277/25841 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 0.99999826926484

Ranking 342/18225 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 0.94270422777329

Ranking 15407/18665 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
Larsen Cumulative Evidence Score

Score 3

Ranking 366/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.39849210242787

Ranking 1480/20870 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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