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

GWIPS-viz	Trips-Viz

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		Ribo-Seq
	SRR7808450	PRJNA489895	Mus musculus		Ribo-Seq
	SRR7808451	PRJNA489895	Mus musculus		Ribo-Seq
	SRR7808452	PRJNA489895	Mus musculus		Ribo-Seq
	Run Accession	Study Accession	Scientific Name	Cell Line	Library Type	Treatment	GWIPS-viz	Trips-Viz	Reads	BAM	BigWig (F)	BigWig (R)

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