Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome.
Jérémie CourraudCamille EngelAngélique QuartierNathalie DrouotUrsula HouessouDamien PlassardArthur SorlinElise Brischoux-BoucherEvan GouyLionel Van MaldergemMassimiliano RossiGaëtan LescaPatrick EderyAudrey PutouxFrederic BilanBrigitte Gilbert-DussardierIsis AtallahVera M KalscheuerJean-Louis MandelAmelie PitonPublished in: Molecular psychiatry (2023)
Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD (CELF2, APC2, etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B, an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1-KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.
Keyphrases
- binding protein
- copy number
- intellectual disability
- gene expression
- genome wide
- case report
- wild type
- cell proliferation
- poor prognosis
- genome wide identification
- neural stem cells
- dna methylation
- healthcare
- cell cycle arrest
- bioinformatics analysis
- transcription factor
- social media
- staphylococcus aureus
- single molecule
- replacement therapy
- signaling pathway
- cell death
- extracellular matrix
- heat stress
- heat shock protein
- congenital heart disease
- induced pluripotent stem cells