UPF3BUPF3B, regulator of nonsense mediated mRNA decay
Autism Reports / Total Reports
7 / 19Rare Variants / Common Variants
31 / 0Aliases
UPF3B, HUPF3B, MRXS14, RENT3B, UPF3XAssociated Syndromes
-Chromosome Band
Xq24Associated Disorders
SCZ, ID, ASDRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to UPF3B (19 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 without autism | 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 and neuronal outgrowth | 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 2 clinical units and 216 patients | Chrot E , et al. (2017) | No | Macrocephaly, hypotonia, absent speech |
| 13 | Support | Molecular and Clinical Characterization of a Novel Nonsense Variant in Exon 1 of the UPF3B Gene Found in a Large Spanish Basque Family (MRX82) | Tejada MI , et al. (2019) | No | ASD |
| 14 | Support | Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability | Ibarluzea N , et al. (2020) | No | - |
| 15 | Support | A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks | Domingo D et al. (2020) | Yes | - |
| 16 | Support | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders | Wang T et al. (2020) | Yes | - |
| 17 | Support | - | Valentino F et al. (2021) | Yes | DD |
| 18 | Support | - | Ferruccio Romano et al. (2024) | No | Autistic features, stereotypy, epilepsy/seizures |
| 19 | Support | - | Yasser Al-Sarraj et al. (2024) | Yes | - |
Rare Variants (31)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.1060C>T | p.Arg354Ter | stop_gained | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.1288C>T | p.Arg430Ter | stop_gained | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.1033C>T | p.Arg345Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.1072C>T | p.Arg358Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.1078C>T | p.Arg360Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.1117C>T | p.Arg373Cys | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.807+431G>A | - | splice_site_variant | Familial | Maternal | - | 28708303 | Chrot E , et al. (2017) | |
| c.1288C>T | p.Arg430Ter | stop_gained | Familial | Maternal | - | 34356170 | Valentino F et al. (2021) | |
| c.764G>A | p.Arg255Lys | missense_variant | Unknown | - | Unknown | 21862950 | Szyszka P , et al. (2011) | |
| c.619A>T | p.Lys207Ter | stop_gained | De novo | - | Simplex | 38318947 | Ferruccio Romano et al. (2024) | |
| c.1266_1269del | p.Glu423LysfsTer8 | frameshift_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
| c.371-1G>C | - | splice_site_variant | Familial | Maternal | Unknown | 31906484 | Ibarluzea N , et al. (2020) | |
| c.1135C>T | p.Arg379Cys | missense_variant | Familial | Maternal | Unknown | 33004838 | Wang T et al. (2020) | |
| - | p.Phe82Leu | missense_variant | Familial | Maternal | Unknown | 38572415 | Yasser Al-Sarraj et al. (2024) | |
| c.883T>A | p.Leu295Met | missense_variant | Familial | Maternal | Simplex | 26544041 | Zhang Y , et al. (2015) | |
| c.177dup | p.Pro60SerfsTer17 | frameshift_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.624G>A | p.Gln208%3D | synonymous_variant | Familial | Maternal | Simplex | 32667670 | Domingo D et al. (2020) | |
| c.1288C>T | p.Arg430Ter | stop_gained | Familial | Maternal | Multi-generational | 22957832 | Xu X , et al. (2012) | |
| c.1118G>A | p.Arg373His | missense_variant | Familial | Maternal | Unknown | 31906484 | Ibarluzea N , et al. (2020) | |
| c.1103G>A | p.Arg368Gln | missense_variant | Familial | Maternal | Simplex | 19238151 | Laumonnier F , et al. (2009) | |
| c.1125_1128del | p.Gln376ArgfsTer17 | frameshift_variant | De novo | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.118C>T | p.Gln40Ter | stop_gained | Familial | Maternal | Multi-generational | 31737052 | Tejada MI , et al. (2019) | |
| c.1288C>T | p.Arg430Ter | stop_gained | Familial | Maternal | Multi-generational | 17704778 | Tarpey PS , et al. (2007) | |
| c.1081C>T | p.Arg361Ter | stop_gained | Familial | Maternal | Multi-generational | 19238151 | Laumonnier F , et al. (2009) | |
| c.1285_1286del | p.Asp429SerfsTer27 | frameshift_variant | De novo | - | Simplex | 38318947 | Ferruccio Romano et al. (2024) | |
| c.697_698del | p.Arg233GlufsTer32 | frameshift_variant | Familial | Maternal | Multiplex | 22609145 | Lynch SA , et al. (2012) | |
| c.674_677del | p.Arg225LysfsTer22 | frameshift_variant | Familial | Maternal | Multiplex | 17704778 | Tarpey PS , et al. (2007) | |
| c.1136G>A | p.Arg379His | missense_variant | Unknown (likely maternal) | - | Multiplex | 19238151 | Laumonnier F , et al. (2009) | |
| c.684_687del | p.Arg229LysfsTer18 | frameshift_variant | Familial | Maternal | Multiplex | 20479756 | Addington AM , et al. (2010) | |
| c.674_677del | p.Arg225LysfsTer22 | frameshift_variant | Familial | Maternal | Simplex | 38318947 | Ferruccio Romano et al. (2024) | |
| c.478T>G | p.Tyr160Asp | missense_variant | Familial | Unknown (likely maternal) | Multi-generational | 17704778 | Tarpey PS , et al. (2007) |
Common Variants
No common variants reported.
SFARI Gene score
High Confidence, Syndromic
Score Delta: Score remained at 1S
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.
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."
10/1/2020
Score remained at 1
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). More recently, a novel nonsense variant in UPF3B was found to completely co-segregate with X-linked intellectual disability in a Spanish Basque family (MRX82); all five affected males in this pedigree showed mild to profound intellectual disability, and two of them were diagnosed with autism spectrum disorder according to the Autism Diagnostic Observation Schedule (ADOS). 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.
7/1/2020
Score remained at 1
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). More recently, a novel nonsense variant in UPF3B was found to completely co-segregate with X-linked intellectual disability in a Spanish Basque family (MRX82); all five affected males in this pedigree showed mild to profound intellectual disability, and two of them were diagnosed with autism spectrum disorder according to the Autism Diagnostic Observation Schedule (ADOS). 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.
1/1/2020
Score remained at 1
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). More recently, a novel nonsense variant in UPF3B was found to completely co-segregate with X-linked intellectual disability in a Spanish Basque family (MRX82); all five affected males in this pedigree showed mild to profound intellectual disability, and two of them were diagnosed with autism spectrum disorder according to the Autism Diagnostic Observation Schedule (ADOS). 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.
10/1/2019
Decreased from 2S to 1
New Scoring Scheme
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). More recently, a novel nonsense variant in UPF3B was found to completely co-segregate with X-linked intellectual disability in a Spanish Basque family (MRX82); all five affected males in this pedigree showed mild to profound intellectual disability, and two of them were diagnosed with autism spectrum disorder according to the Autism Diagnostic Observation Schedule (ADOS). 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.
7/1/2017
Decreased 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
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.
Reports Added
[A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders.2010] [Broadening the phenotype associated with mutations in UPF3B: two further cases with renal dysplasia and variable developmental delay.2012] [Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or withou...2009] [Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree.2012] [Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.2007] [The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour an...2013] [Full UPF3B function is critical for neuronal differentiation of neural stem cells.2015] [A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]1/1/2016
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).
Reports Added
[A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders.2010] [Broadening the phenotype associated with mutations in UPF3B: two further cases with renal dysplasia and variable developmental delay.2012] [Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or withou...2009] [Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree.2012] [Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.2007] [The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour an...2013] [Full UPF3B function is critical for neuronal differentiation of neural stem cells.2015] [A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia.2011] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]4/1/2015
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]
ExAC Score
Score 0.93376690112975
Ranking 2893/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.41450517875315
Ranking 298/18665 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.47479472817593
Ranking 704/20870 scored genes
[Show Scoring Methodology]
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 |
|---|---|---|---|---|---|
| ZNF280A | Zinc finger protein 280A | Human | Protein Binding | 129025 | P59817 |