Zhao et al. 2019 (PRJNA489895)

General Details

Title Ribosome profiling of selenoproteins in vivo reveals consequences of pathogenic Secisbp2 missense mutations
Organism
Number of Samples 4
Release Date 2018/09/07 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP160398
ENA SRP160398
GEO GSE119681
BioProject PRJNA489895

Publication

Title
Authors Zhao W, Bohleber S, Schmidt H, Seeher S, Howard MT, Braun D, Arndt S, Reuter U, Wende H, Birchmeier C, Fradejas-Villar N, Schweizer U
Journal The Journal of biological chemistry
Publication Date 2019 Sep 27
Abstract Recoding of UGA codons as selenocysteine (Sec) codons in selenoproteins depends on a selenocysteine insertion sequence (SECIS) in the 3'-UTR of mRNAs of eukaryotic selenoproteins. SECIS-binding protein 2 (SECISBP2) increases the efficiency of this process. Pathogenic mutations in SECISBP2 reduce selenoprotein expression and lead to phenotypes associated with the reduction of deiodinase activities and selenoprotein N expression in humans. Two functions have been ascribed to SECISBP2: binding of SECIS elements in selenoprotein mRNAs and facilitation of co-translational Sec insertion. To separately probe both functions, we established here two mouse models carrying two pathogenic missense mutations in Secisbp2 previously identified in patients. We found that the C696R substitution in the RNA-binding domain abrogates SECIS binding and does not support selenoprotein translation above the level of a complete Secisbp2 null mutation. The R543Q missense substitution located in the selenocysteine insertion domain resulted in residual activity and caused reduced selenoprotein translation, as demonstrated by ribosomal profiling to determine the impact on UGA recoding in individual selenoproteins. We found, however, that the R543Q variant is thermally unstable in vitro and completely degraded in the mouse liver in vivo , while being partially functional in the brain. The moderate impairment of selenoprotein expression in neurons led to astrogliosis and transcriptional induction of genes associated with immune responses. We conclude that differential SECISBP2 protein stability in individual cell types may dictate clinical phenotypes to a much greater extent than molecular interactions involving a mutated amino acid in SECISBP2. © 2019 Zhao et al.
PMC PMC6768643
PMID 31350336
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR7808449 PRJNA489895 Mus musculus 0.0 Ribo-Seq 0.0
SRR7808450 PRJNA489895 Mus musculus 0.0 Ribo-Seq 0.0
SRR7808451 PRJNA489895 Mus musculus 0.0 Ribo-Seq 0.0
SRR7808452 PRJNA489895 Mus musculus 0.0 Ribo-Seq 0.0
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

ⓘ For more Information on the columns shown here see: About