PMID- 38030819 OWN - NLM STAT- Publisher LR - 20231129 IS - 1476-5578 (Electronic) IS - 1359-4184 (Linking) DP - 2023 Nov 29 TI - Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome. LID - 10.1038/s41380-023-02323-5 [doi] AB - 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. CI - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited. FAU - Courraud, Jeremie AU - Courraud J AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Engel, Camille AU - Engel C AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Quartier, Angelique AU - Quartier A AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Drouot, Nathalie AU - Drouot N AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Houessou, Ursula AU - Houessou U AUID- ORCID: 0009-0002-8716-3007 AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Plassard, Damien AU - Plassard D AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Sorlin, Arthur AU - Sorlin A AUID- ORCID: 0000-0001-8008-9145 AD - National Center of Genetics, Laboratoire national de sante, Dudelange, Luxembourg. FAU - Brischoux-Boucher, Elise AU - Brischoux-Boucher E AD - Centre de Genetique Humaine, CHU Besancon, Universite de Franche-Comte, 25056, Besancon, France. FAU - Gouy, Evan AU - Gouy E AD - Genetics Department, University Hospital of Lyon, Bron, 69500, France. FAU - Van Maldergem, Lionel AU - Van Maldergem L AD - Centre de Genetique Humaine, CHU Besancon, Universite de Franche-Comte, 25056, Besancon, France. FAU - Rossi, Massimiliano AU - Rossi M AUID- ORCID: 0000-0002-5797-8152 AD - Genetics Department, University Hospital of Lyon, Bron, 69500, France. AD - Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France. FAU - Lesca, Gaetan AU - Lesca G AUID- ORCID: 0000-0001-7691-9492 AD - Genetics Department, University Hospital of Lyon, Bron, 69500, France. AD - Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France. FAU - Edery, Patrick AU - Edery P AD - Genetics Department, University Hospital of Lyon, Bron, 69500, France. AD - Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France. FAU - Putoux, Audrey AU - Putoux A AD - Genetics Department, University Hospital of Lyon, Bron, 69500, France. AD - Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France. FAU - Bilan, Frederic AU - Bilan F AD - Service de genetique medicale, CHU de Poitiers, 86 000, Poitiers, France. FAU - Gilbert-Dussardier, Brigitte AU - Gilbert-Dussardier B AD - Service de genetique medicale, CHU de Poitiers, 86 000, Poitiers, France. FAU - Atallah, Isis AU - Atallah I AUID- ORCID: 0000-0002-0618-1549 AD - Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. FAU - Kalscheuer, Vera M AU - Kalscheuer VM AUID- ORCID: 0000-0001-6898-3259 AD - Max Planck Institute for Molecular Genetics, Berlin, Germany. FAU - Mandel, Jean-Louis AU - Mandel JL AUID- ORCID: 0000-0002-0535-6589 AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. AD - Universite de Strasbourg, 67 400, Illkirch, France. FAU - Piton, Amelie AU - Piton A AUID- ORCID: 0000-0003-0408-7468 AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, France. apiton@unistra.fr. AD - Centre National de la Recherche Scientifique, UMR7104, Illkirch, France. apiton@unistra.fr. AD - Institut National de la Sante et de la Recherche Medicale, U964, Illkirch, France. apiton@unistra.fr. AD - Universite de Strasbourg, 67 400, Illkirch, France. apiton@unistra.fr. AD - Genetic diagnosis laboratory, Strasbourg University Hospital, 67 090, Strasbourg, France. apiton@unistra.fr. AD - Institut Universitaire de France, Paris, France. apiton@unistra.fr. LA - eng PT - Journal Article DEP - 20231129 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 SB - IM EDAT- 2023/11/30 00:42 MHDA- 2023/11/30 00:42 CRDT- 2023/11/29 23:37 PHST- 2023/01/12 00:00 [received] PHST- 2023/11/13 00:00 [accepted] PHST- 2023/10/18 00:00 [revised] PHST- 2023/11/30 00:42 [medline] PHST- 2023/11/30 00:42 [pubmed] PHST- 2023/11/29 23:37 [entrez] AID - 10.1038/s41380-023-02323-5 [pii] AID - 10.1038/s41380-023-02323-5 [doi] PST - aheadofprint SO - Mol Psychiatry. 2023 Nov 29. doi: 10.1038/s41380-023-02323-5.