Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome.

Autor: Courraud J; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Engel C; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Quartier A; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Drouot N; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Houessou U; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Plassard D; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Sorlin A; National Center of Genetics, Laboratoire national de santé, Dudelange, Luxembourg., Brischoux-Boucher E; Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25056, Besançon, France., Gouy E; Genetics Department, University Hospital of Lyon, Bron, 69500, France., Van Maldergem L; Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25056, Besançon, France., Rossi M; Genetics Department, University Hospital of Lyon, Bron, 69500, France.; Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France., Lesca G; Genetics Department, University Hospital of Lyon, Bron, 69500, France.; Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France., Edery P; Genetics Department, University Hospital of Lyon, Bron, 69500, France.; Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France., Putoux A; Genetics Department, University Hospital of Lyon, Bron, 69500, France.; Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France., Bilan F; Service de génétique médicale, CHU de Poitiers, 86 000, Poitiers, France., Gilbert-Dussardier B; Service de génétique médicale, CHU de Poitiers, 86 000, Poitiers, France., Atallah I; Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland., Kalscheuer VM; Max Planck Institute for Molecular Genetics, Berlin, Germany., Mandel JL; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.; Université de Strasbourg, 67 400, Illkirch, France., Piton A; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. apiton@unistra.fr.; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. apiton@unistra.fr.; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France. apiton@unistra.fr.; Université de Strasbourg, 67 400, Illkirch, France. apiton@unistra.fr.; Genetic diagnosis laboratory, Strasbourg University Hospital, 67 090, Strasbourg, France. apiton@unistra.fr.; Institut Universitaire de France, Paris, France. apiton@unistra.fr.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Feb; Vol. 29 (2), pp. 287-296. Date of Electronic Publication: 2023 Nov 29.
DOI: 10.1038/s41380-023-02323-5
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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