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

Molecular Psychiatry (2023)Cite this article

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Abstract

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.

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Fig. 1: Consequences of PQBP1 Knock-Down (KD) in human neural stem cells (hNSC).
Fig. 2: Expression of a non-canonical isoform of UPF3B (UPF3B_S) is increased after PQBP1-KD.
Fig. 3: Increase of UPF3B_S is a molecular marker for Renpenning syndrome.

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Data availability

Data have been submitted to Gene Expression Omnibus (GSE247739).

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Acknowledgements

The authors would like to thank the families for their participation and support. The authors also thank the Agence de Biomédecine, Fondation APLM for financial support, as well as Besançon Hospital and University for Camille Engel’s fellowship. We also thank the GenomEast sequencing platform for performing RNASeq and for their help in data analysis, as well as Bastien Morlet from the Mass spectrometry platform and Anne Maglott from the high-throughput screening platform. We thank Camille Dourlens for her participation to the project as well as Josef Gecz, Frederic Laumonnier, Renaud Touraine and David Germanaud for scientific discussion and advice.

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Author notes

  1. These authors contributed equally: Camille Engel, Angélique Quartier, Nathalie Drouot.

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Jérémie Courraud, Camille Engel, Angélique Quartier, Nathalie Drouot, Ursula Houessou, Damien Plassard, Jean-Louis Mandel & Amélie Piton

  2. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France

    Jérémie Courraud, Camille Engel, Angélique Quartier, Nathalie Drouot, Ursula Houessou, Damien Plassard, Jean-Louis Mandel & Amélie Piton

  3. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France

    Jérémie Courraud, Camille Engel, Angélique Quartier, Nathalie Drouot, Ursula Houessou, Damien Plassard, Jean-Louis Mandel & Amélie Piton

  4. Université de Strasbourg, 67 400, Illkirch, France

    Jérémie Courraud, Camille Engel, Angélique Quartier, Nathalie Drouot, Ursula Houessou, Damien Plassard, Jean-Louis Mandel & Amélie Piton

  5. National Center of Genetics, Laboratoire national de santé, Dudelange, Luxembourg

    Arthur Sorlin

  6. Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25056, Besançon, France

    Elise Brischoux-Boucher & Lionel Van Maldergem

  7. Genetics Department, University Hospital of Lyon, Bron, 69500, France

    Evan Gouy, Massimiliano Rossi, Gaetan Lesca, Patrick Edery & Audrey Putoux

  8. Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France

    Massimiliano Rossi, Gaetan Lesca, Patrick Edery & Audrey Putoux

  9. Service de génétique médicale, CHU de Poitiers, 86 000, Poitiers, France

    Frederic Bilan & Brigitte Gilbert-Dussardier

  10. Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland

    Isis Atallah

  11. Max Planck Institute for Molecular Genetics, Berlin, Germany

    Vera M. Kalscheuer

  12. Genetic diagnosis laboratory, Strasbourg University Hospital, 67 090, Strasbourg, France

    Amélie Piton

  13. Institut Universitaire de France, Paris, France

    Amélie Piton

Authors
  1. Jérémie Courraud
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  2. Camille Engel
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Contributions

Experiment realization: JC, CE, AQ, ND, UH, AP; Acquisition of molecular and clinical genetic data: CE, AS, EBB, EG, LVM, MR, GL, PE, FB, BGD, IA, VMK, AP, JLM; Data analysis : JC, CE, AQ, ND, UH, DP; Writing and editing manuscript: JC, VMK, AP, JLM, Conceptualization and supervision: AP; Funding acquisition: AP, JLM.

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Correspondence to Amélie Piton.

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Individuals were referred by clinical geneticists for genetic testing as part of routine clinical care. All patients enrolled and/or their legal representative have signed informed consent for research use and authorization for publication. IRB approval was obtained from the Ethics Committee of the Strasbourg University Hospital (CCPPRB) as well as from local institutions.

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Courraud, J., Engel, C., Quartier, A. et al. Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02323-5

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