Human Gene Module / Chromosome X / UPF3B

UPF3BUPF3B, regulator of nonsense mediated mRNA decay

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 12
Rare Variants / Common Variants
14 / 0
Aliases
UPF3B, HUPF3B,  MRXS14,  RENT3B,  UPF3X
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xq24
Associated Disorders
SCZ, ID, ASD
Relevance to Autism

Defects in UPF3B are the cause of a syndromic form of mental retardation, mental retardation syndromic X-linked type 14 (MRXS14) [MIM:300676]. A subset of individuals with MRXS14 are also either diagnosed with autism or are found to exhibit autistic features (Tarpey et al., 2007; Laumonnier et al., 2010; Addington et al., 2011; Lynch et al., 2012).

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. The encoded protein is one of two functional homologs to yeast Upf3p. 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 binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions.

Reports related to UPF3B (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Tarpey PS , et al. (2007) No Autistic features
2 Recent Recommendation Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or withou... Laumonnier F , et al. (2009) No ID, ASD
3 Recent Recommendation A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Addington AM , et al. (2010) Yes SCZ
4 Support A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia. Szyszka P , et al. (2011) No -
5 Recent Recommendation Broadening the phenotype associated with mutations in UPF3B: two further cases with renal dysplasia and variable developmental delay. Lynch SA , et al. (2012) No ASD or autistic features
6 Support Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree. Xu X , et al. (2012) No -
7 Recent Recommendation The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour an... Jolly LA , et al. (2013) No -
8 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
9 Recent Recommendation Full UPF3B function is critical for neuronal differentiation of neural stem cells. Alrahbeni T , et al. (2015) No -
10 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
11 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
12 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No Macrocephaly, hypotonia, absent speech
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.674_677delGAAA p.Arg225fsTer20 frameshift_variant Familial Maternal Multiplex 17704778 Tarpey PS , et al. (2007)
c.1288C>T p.Arg430Ter stop_gained Familial Maternal Extended 17704778 Tarpey PS , et al. (2007)
c.478T>G p.Tyr160Asp missense_variant Familial Unknown (likely maternal) Extended 17704778 Tarpey PS , et al. (2007)
c.1081C>T p.Arg361Ter stop_gained Familial Maternal Extended 19238151 Laumonnier F , et al. (2009)
c.1136G>A p.Arg379His missense_variant Unknown (likely maternal) - Multiplex 19238151 Laumonnier F , et al. (2009)
c.1103G>A p.Arg368Gln missense_variant Familial Maternal Simplex 19238151 Laumonnier F , et al. (2009)
c.683_686delAAGA p.Gln228fsTer18 frameshift_variant Familial Maternal Multiplex 20479756 Addington AM , et al. (2010)
c.764G>A p.Arg255Lys missense_variant Unknown - Unknown 21862950 Szyszka P , et al. (2011)
c.697_698delAG p.Arg233fsTer30 frameshift_variant Familial Maternal Multiplex 22609145 Lynch SA , et al. (2012)
c.1288C>T p.Arg430Ter stop_gained Familial Maternal Multi-generational 22957832 Xu X , et al. (2012)
insA - frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.883T>A p.Leu295Met missense_variant Familial Maternal Simplex 26544041 Zhang Y , et al. (2015)
c.1125_1128del;c.1164_1167del p.Arg375fs;p.Arg388fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.846+1G>A p.? splice_site_variant Familial Maternal - 28708303 Chrot E , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Increased from 2S to 3.3 + acc + S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2018
2S
icon
3.3 + acc + S

Increased from 2S to 3.3 + acc + S

Description

2S

7/1/2017
2S
icon
2S

Increased from 2S to 2S

Description

Defects in UPF3B are the cause of a syndromic form of mental retardation, mental retardation syndromic X-linked type 14 (MRXS14) [MIM:300676]. A subset of individuals with MRXS14 are also either diagnosed with autism or are found to exhibit autistic features (PMIDs 17704778, 19238151, 20479756 and 22609145). De novo loss-of-function variants in UPF3B have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and from the Baby Siblings Research Consortium cohort by whole genome sequencing as part of the MSSNG initiative (Yuen et al., 2017). Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), UPF3B was determined to be an ASD candidate gene in Yuen et al., 2017.

4/1/2017
S
icon
2S

Increased from S to 2S

Description

Defects in UPF3B are the cause of a syndromic form of mental retardation, mental retardation syndromic X-linked type 14 (MRXS14) [MIM:300676]. A subset of individuals with MRXS14 are also either diagnosed with autism or are found to exhibit autistic features (PMIDs 17704778, 19238151, 20479756 and 22609145). De novo loss-of-function variants in UPF3B have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014) and from the Baby Siblings Research Consortium cohort by whole genome sequencing as part of the MSSNG initiative (Yuen et al., 2017). Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), UPF3B was determined to be an ASD candidate gene in Yuen et al., 2017.

1/1/2016
S
icon
S

Increased from S to S

Description

Defects in UPF3B are the cause of a syndromic form of mental retardation, mental retardation syndromic X-linked type 14 (MRXS14) [MIM:300676]. A subset of individuals with MRXS14 are also either diagnosed with autism or are found to exhibit autistic features (PMIDs 17704778, 19238151, 20479756 and 22609145).

4/1/2015
S
icon
S

Increased from S to S

Description

Defects in UPF3B are the cause of a syndromic form of mental retardation, mental retardation syndromic X-linked type 14 (MRXS14) [MIM:300676]. A subset of individuals with MRXS14 are also either diagnosed with autism or are found to exhibit autistic features (PMIDs 17704778, 19238151, 20479756 and 22609145).

Krishnan Probability Score

Score 0.42128378452648

Ranking 21134/25841 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 0.93376690112975

Ranking 2893/18225 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 0.41450517875315

Ranking 298/18665 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 0.47479472817593

Ranking 704/20870 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.
CNVs associated with UPF3B(1 CNVs)
Xq24 12 Deletion-Duplication 17  /  45
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ZNF280A Zinc finger protein 280A Human Protein Binding 129025 P59817
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