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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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.
X-linked syndromic mental retardation-14 (MRXS14)
Autistic features
Support
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations
ASD, ID
DD
Support
Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.
DD, ID, epilepsy/seizures
Support
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
ASD, DD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
A synonymous UPF3B variant causing a speech disorder implicates NMD as a regulator of neurodevelopmental disorder gene networks
ASD, DD
Support
Exome sequencing identifies UPF3B as the causative gene for a Chinese non-syndrome mental retardation pedigree.
ID
Support
Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.
ID
Support
Unveiling genetic insights: Array-CGH and WES discoveries in a cohort of 122 children with essential autism spectrum disorder
ASD
Support
A nonconservative amino acid change in the UPF3B gene in a patient with schizophrenia.
SCZ
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).
ID
ASD
Support
The genetic landscape of autism spectrum disorder in the Middle Eastern population
ASD
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
Macrocephaly, hypotonia, absent speech
Support
Expanding the phenotype of UPF3B-related disorder: Case reports and literature review
DD, ID
Autistic features, stereotypy, epilepsy/seizures
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Recent Recommendation
Broadening the phenotype associated with mutations in UPF3B: two further cases with renal dysplasia and variable developmental delay.
DD, ID
ASD or autistic features
Recent Recommendation
A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders.
ASD, ADHD
SCZ
Recent Recommendation
Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or withou...
X-linked syndromic mental retardation-14 (MRXS14)
ID, ASD
Recent Recommendation
Full UPF3B function is critical for neuronal differentiation of neural stem cells.
Recent Recommendation
The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour an...

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN364R001 
 frameshift_variant 
 c.674_677del 
 p.Arg225LysfsTer22 
 Familial 
 Maternal 
 Multiplex 
 GEN364R002 
 stop_gained 
 c.1288C>T 
 p.Arg430Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN364R003 
 missense_variant 
 c.478T>G 
 p.Tyr160Asp 
 Familial 
 Unknown (likely maternal) 
 Multi-generational 
 GEN364R004 
 stop_gained 
 c.1081C>T 
 p.Arg361Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN364R005 
 missense_variant 
 c.1136G>A 
 p.Arg379His 
 Unknown (likely maternal) 
  
 Multiplex 
 GEN364R006 
 missense_variant 
 c.1103G>A 
 p.Arg368Gln 
 Familial 
 Maternal 
 Simplex 
 GEN364R007 
 frameshift_variant 
 c.684_687del 
 p.Arg229LysfsTer18 
 Familial 
 Maternal 
 Multiplex 
 GEN364R008 
 frameshift_variant 
 c.697_698del 
 p.Arg233GlufsTer32 
 Familial 
 Maternal 
 Multiplex 
 GEN364R009 
 stop_gained 
 c.1288C>T 
 p.Arg430Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN364R010 
 missense_variant 
 c.764G>A 
 p.Arg255Lys 
 Unknown 
  
 Unknown 
 GEN364R011 
 frameshift_variant 
 c.177dup 
 p.Pro60SerfsTer17 
 De novo 
  
 Simplex 
 GEN364R012 
 missense_variant 
 c.883T>A 
 p.Leu295Met 
 Familial 
 Maternal 
 Simplex 
 GEN364R013 
 frameshift_variant 
 c.1125_1128del 
 p.Gln376ArgfsTer17 
 De novo 
  
 Simplex 
 GEN364R014 
 splice_site_variant 
 c.807+431G>A 
  
 Familial 
 Maternal 
  
 GEN364R015 
 splice_site_variant 
 c.807+431G>A 
  
 Familial 
 Maternal 
  
 GEN364R016 
 stop_gained 
 c.118C>T 
 p.Gln40Ter 
 Familial 
 Maternal 
 Multi-generational 
 GEN364R017 
 splice_site_variant 
 c.371-1G>C 
  
 Familial 
 Maternal 
 Unknown 
 GEN364R018 
 missense_variant 
 c.1118G>A 
 p.Arg373His 
 Familial 
 Maternal 
 Unknown 
 GEN364R019 
 synonymous_variant 
 c.624G>A 
 p.Gln208= 
 Familial 
 Maternal 
 Simplex 
 GEN364R020 
 stop_gained 
 c.1060C>T 
 p.Arg354Ter 
 Unknown 
  
  
 GEN364R021 
 missense_variant 
 c.1135C>T 
 p.Arg379Cys 
 Familial 
 Maternal 
 Unknown 
 GEN364R022 
 stop_gained 
 c.1288C>T 
 p.Arg430Ter 
 Unknown 
  
  
 GEN364R023 
 frameshift_variant 
 c.1266_1269del 
 p.Glu423LysfsTer8 
 Unknown 
  
  
 GEN364R024 
 missense_variant 
 c.1078C>T 
 p.Arg360Cys 
 Unknown 
  
  
 GEN364R025 
 missense_variant 
 c.1117C>T 
 p.Arg373Cys 
 Unknown 
  
  
 GEN364R026 
 missense_variant 
 c.1033C>T 
 p.Arg345Cys 
 Unknown 
  
  
 GEN364R027 
 missense_variant 
 c.1072C>T 
 p.Arg358Cys 
 Unknown 
  
  
 GEN364R028 
 stop_gained 
 c.1288C>T 
 p.Arg430Ter 
 Familial 
 Maternal 
  
 GEN364R029 
 stop_gained 
 c.619A>T 
 p.Lys207Ter 
 De novo 
  
 Simplex 
 GEN364R030 
 frameshift_variant 
 c.1285_1286del 
 p.Asp429SerfsTer27 
 De novo 
  
 Simplex 
 GEN364R031 
 frameshift_variant 
 c.674_677del 
 p.Arg225LysfsTer22 
 Familial 
 Maternal 
 Simplex 
 GEN364R032 
 missense_variant 
  
 p.Phe82Leu 
 Familial 
 Maternal 
 Unknown 
 GEN364R033 
 missense_variant 
 c.931C>T 
 p.Arg311Cys 
 Familial 
 Maternal 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 22
 
X
Deletion
 2
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion
 2
 
X
Deletion-Duplication
 13
 
X
Deletion
 5
 

M_UPF3B_1_KO_HM_HALOPERIDOL

Rescue Type: RESCUE-Pharmaceutical
Rescue Paradigm: ESC clone harboring gene trap cassette insertion in intron 1 was used to inject into donor blastocysts to generate chimeric Upf3b-mutant mice. Global Upf3b-mutant mice were obtained following breeding for germline transmission.

M_UPF3B_1_KO_HM_HALOPERIDOL

Category
Entity
Effect on phenotype Qualification
Restored Treatment improves measured phenotype significantly
Refractory Treatment does not improve measured phenotype (was expected to do so)
Ameliorated Treatment provides partial correction or improvement of measured phenotype
No adverse effect Treatment does not affect the parameter adversely
Sustained effect Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Unexpected results Treats an unexpected phenotype
Side effect Exaggerates an unexpected phenotype
Experimental Paradigm
Age at Testing
Sensorimotor gating1
Refractory
Description: Haloperidol has no significant effect on prepulse inhibition in upf3b-mutant mice at any dose (0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg) or across different pulse intensities (78-86 db) and prepulse intervals (25-500 ms) tested.
Exp Paradigm: NA
 Prepulse inhibition
 8-11 weeks
Startle response: acoustic stimulus1
Refractory
Description: Haloperidol has no significant effect on startle magnitude in upf3b-mutant mice at any dose (0.1 mg/kg, 0.3 mg/kg, or 1 mg/kg) or across different pulse intensities (90-120 db) tested.
Exp Paradigm: NA
 Startle response test
 8-11 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Social behavior

M_UPF3B_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
 Sleep pattern1
 Abnormal
Description: Upf3b-mutant mice show abnormal sleep behaviors compared to controls. specifically, upf3b-mutant mice differ from the control mice in time spent in wakefulness, slow wave sleep, and rem sleep. moreover, upf3b-mutant mice had more episodes of vigilance states that the average episode durations were shorter compared to conrols.
Exp Paradigm: NA
 Electroencephalogram (eeg)
 8-11 weeks
 Clasping reflex1
 Abnormal
Description: Upf3b-mutant mice show abnormal paw-clasping behavior compared to controls. specifically, significantly more upf3b-mutant mice engage in no paw-clasping behavior, significantly fewer upf3b-mutant mice engage in occasional front paw-clasping behavior, and significantly more upf3b-mutant mice engage in frequent front paw-clasping behavior compared to controls.
Exp Paradigm: NA
 Tail suspension test
 8-11 weeks
 Dendritic architecture: spine morphology1
 Abnormal
Description: Upf3b-mutant mice show reduction in the number of mature dendritic spines but no difference in the number of immature spines compared to controls.
Exp Paradigm: NA
 Golgi-cox staining
 8-11 weeks
 Dendritic architecture: spine density1
 Decreased
Description: Upf3b-mutant mice show reduction in dendritic spine density in cortical pyramidal neurons and dentate granule cells of the hippicampus but not the hippocampal ca1 pyramidal neurons compared to controls.
Exp Paradigm: NA
 Golgi-cox staining
 8-11 weeks
 Startle response: acoustic stimulus1
 Decreased
Description: Upf3b-mutant mice show deficiency in the magnitude of the acoustic startle response compared to controls. specifically, their deficiency is specific to low intensity 90-100 db range pulses, whereas they respond normally to 115-120 db range pulses.
Exp Paradigm: NA
 Startle response test
 8-11 weeks
 Sensorimotor gating1
 Decreased
Description: Upf3b-mutant mice show profound defect in prepulse inhibition compared to controls. specifically, upf3b-mutant mice show lower prepulse inhbition across different pulse intensities (78 db, 82 db, and 86 db) as well as across different 25-500 ms prepulse intervals compared to controls.
Exp Paradigm: NA
 Prepulse inhibition
 8-11 weeks
 Cued or contextual fear conditioning: memory of cue1
 Decreased
Description: Upf3b-mutant mice show less freezing in the cue test in cued fear conditioning compared to controls.
Exp Paradigm: NA
 Fear conditioning test
 8-11 weeks
 Cued or contextual fear conditioning: memory of context1
 Decreased
Description: Upf3b-mutant mice show less freezing in the context test in contextual fear conditioning compared to controls.
Exp Paradigm: NA
 Fear conditioning test
 8-11 weeks
 Targeted expression1
 Decreased
Description: Upf3b-mutant mice show no detectable levels of upf3b protein in the whole brain, hippocampus, or cerebral cortex compared to controls.
Exp Paradigm: Immunofluorescence staining
 Immunofluorescence staining
 8-11 weeks
 Gene expression1
 Abnormal
Description: Upf3b-mutant mice show a total of 129 misregulated genes, 109 of which are upregulated and 20 downregulated compared to controls.
Exp Paradigm: NA
 Rna sequencing
 8-11 weeks
 Targeted expression1
 Decreased
Description: Upf3b-mutant mice show over 100-fold decrease in upf3b mrna expression in most tissues compared to controls.
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 8-11 weeks
 Targeted expression1
 Decreased
Description: Upf3b-mutant mice show no detectable levels of upf3b protein in the whole brain, hippocampus, or cerebral cortex compared to controls.
Exp Paradigm: Western blot
 Western blot
 8-11 weeks
Anxiety1
 No change
 Light-dark exploration test
 8-11 weeks
Spatial reference memory1
 No change
 Y-maze test
 8-11 weeks
Spatial working memory1
 No change
 Barnes maze test
 8-11 weeks
General locomotor activity: ambulatory activity1
 No change
 Three-chamber social approach test
 8-11 weeks
Hearing1
 No change
 Auditory brainstem response test
 8-11 weeks
Vision1
 No change
 Ophthalmological evaluation
 8-11 weeks
 Not Reported: Communications, Developmental profile, Immune response, Maternal behavior, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Social behavior





Download UPF3B's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
CAND1 cullin-associated and neddylation-dissociated 1 55832 Q86VP6 IP; MS
Bennett EJ , et al. 2010
CASC3 cancer susceptibility candidate 3 22794 O15234 X-ray crystallography
Buchwald G , et al. 2010
CCDC60 Coiled-coil domain-containing protein 60 160777 Q8IWA6 IP; LC-MS/MS
Huttlin EL , et al. 2015
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
COPS5 COP9 constitutive photomorphogenic homolog subunit 5 (Arabidopsis) 10987 Q92905 IP; MS
Bennett EJ , et al. 2010
CUL5 cullin 5 8065 Q93034 IP; MS
Bennett EJ , et al. 2010
DEFA5 Defensin-5 1670 Q01523 IP; LC-MS/MS
Huttlin EL , et al. 2015
EIF4A3 eukaryotic translation initiation factor 4A3 9775 P38919 IP/WB
Sato H and Maquat LE 2009
EIF6 eukaryotic translation initiation factor 6 3692 P56537 Y2H
Stelzl U , et al. 2005
FADS3 SLC24A2 3995 Q9Y5Q0 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
HBB hemoglobin, beta 3043 D9YZU5 IP; RNase protection assay
Lykke-Andersen J , et al. 2001
KIAA0101 KIAA0101 9768 A6NNU5 IP; MS
Emanuele MJ , et al. 2011
MAGOHB mago-nashi homolog B (Drosophila) 55110 Q96A72 X-ray crystallography
Buchwald G , et al. 2010
MCRS1 microspherule protein 1 10445 Q96EZ8 Y2H
Lehner B and Sanderson CM 2004
RBM8A RNA binding motif protein 8A 9939 Q9Y5S9 IP/WB
Gehring NH , et al. 2003
RLIM ring finger protein, LIM domain interacting 51132 Q9NVW2 IP; LC-MS/MS
Huttlin EL , et al. 2015
SMG1 smg-1 homolog, phosphatidylinositol 3-kinase-related kinase (C. elegans) 23049 Q96Q15 IP/WB
Kashima I , et al. 2006
SMG6 smg-6 homolog, nonsense mediated mRNA decay factor (C. elegans) 23293 B7Z874 IP/WB
Chiu SY , et al. 2003
TTC19 tetratricopeptide repeat domain 19 54902 Q6DKK2 Y2H
Lehner B and Sanderson CM 2004
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010
UPF1 UPF1 regulator of nonsense transcripts homolog (yeast) 5976 Q92900 IP/WB
Lykke-Andersen J , et al. 2001
UPF2 UPF2 regulator of nonsense transcripts homolog (yeast) 26019 Q9HAU5 IP/WB
Lykke-Andersen J , et al. 2001
UPF3A UPF3 regulator of nonsense transcripts homolog A (yeast) 65110 Q9H1J1 IP/WB
Lejeune F , et al. 2003
USP21 ubiquitin specific peptidase 21 27005 Q9UK80 IP; MS; COMPASS
Sowa ME , et al. 2009
ZNF280A Zinc finger protein 280A 129025 P59817 IP; LC-MS/MS
Huttlin EL , et al. 2015
Rbfox1 RNA binding protein, fox-1 homolog (C. elegans) 1 268859 Q9JJ43 HITS-CLIP
Weyn-Vanhentenryck SM , et al. 2014
ALYREF Aly/REF export factor 10189 E9PB61 IP/WB
Lejeune F , et al. 2002
DCP2 N/A 694225 G7MVJ6 IP/WB
Lejeune F , et al. 2003
EXOSC10 N/A 714153 F6S2L0 IP/WB
Lejeune F , et al. 2003
EXOSC2 N/A 715960 F7EH95 IP/WB
Lejeune F , et al. 2003
EXOSC4 N/A 700012 F7DHI6 IP/WB
Lejeune F , et al. 2003
NCBP1 N/A 718256 N/A IP/WB
Lejeune F , et al. 2002
NXF1 N/A 718420 N/A IP/WB
Lejeune F , et al. 2002
PARN poly(A)-specific ribonuclease 5073 B3KN69 IP/WB
Lejeune F , et al. 2003
RNPS1 RNA binding protein S1, serine-rich domain 10921 D3DU92 IP/WB
Lejeune F , et al. 2002
SRRM1 serine/arginine repetitive matrix 1 10250 Q8IYB3 IP/WB
Lejeune F , et al. 2002
XRN1 5'-3' exoribonuclease 1 714497 F7APA3 IP/WB
Lejeune F , et al. 2003
XRN2 N/A 700934 N/A IP/WB
Lejeune F , et al. 2003

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