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
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders.
Mice lacking Upf2 in the forebrain show impaired nonsense mediated decay, impaired cognitive flexibility, memory deficits, abnormal long-term potentiation, social and communication deficits, increased expression of immune genes and brain inflammation. Chronic treatment with two FDA-approved anti-inflammatory drugs, CyP and Mino, reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits.
References
Type
Title
Author, Year
Primary
Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response.
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with conditional deletion of Upf2 in the forebrain with loxp sites flanking exons 2, containing the initiating ATG, and 3 (Weischenfeldt et al., 2008) through CamKII-Cre (forebrain Cre driver, JAX: 027400) mediated excision. Control littermates included Upf2^wt/wt, Upf2^wt/wt; Camk2a-Cre mice, and Upf2^loxP/loxP mice.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL/6J
ES Cell Line: Mutant ES Cell Line: Model Source: Weischenfeldt et al., 2008; Dragatsis and Zeitlin, 2000
Ultrasonic vocalization: interaction induced: same sex stimulus1
Decreased
Description: Mutants emit fewer interaction-induced usvs in same-sex adult female pairs. mutants show more complex and louder call patterns.
Exp Paradigm: NA
Description: Mutants show increase in the pro-inflammatory cytokine rantes and the t cell chemoattractants ip-10 and mig only in the forebrain.
Exp Paradigm: NA
Description: Mutants show increase in the total number of immune cells in the brain including cd11b, b220 positive b cells. mutants show no change in immune cells in the spleen.
Exp Paradigm: NA
Description: Mutants show increase in the total number of immune cells in the brain including ly6g positive neutrophils. mutants show no change in immune cells in the spleen.
Exp Paradigm: NA
Description: Mutants show increase in the total number of immune cells in the brain including cd3 positive t cells. mutants show no change in immune cells in the spleen. mutant but not control brain lysates increase control t cell proliferation.
Exp Paradigm: NA
Description: Mutants show decrease in upf2 transcript levels in the hippocampus and cerebral cortex but not in the cerebellum. mutants show decrease in upf2 transcript at 3 months but not at 1 month in the hippocampus.
Exp Paradigm: NA
Description: Mutants show nmd mrna substrates atf4, gadd45b, pdrg1, cars, ddit3, and rassf1 were all significantly upregulated in the hippocampus and cortex but not in the cerebellum. mutants show no change in transcript levels of non-nmd targets gapdh, vsp4a, and srp72 in the cortex and hippocampus. mutants show increased expression of approximately 300 genes at steady state including immune related genes.
Exp Paradigm: NA
