RBMX functional retrocopy safeguards brain development

medRxiv

Abstract

ABSTRACT Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. Here we uncover a critical role for RBMX retrocopy in shaping neurodevelopment and modulating disease. Pathogenic variants in RBMX , an X-linked splicing regulator, cause intellectual disability, microcephaly, and cortical malformations. Through integrated human genetic, cellular, and mouse model studies, we show that RBMX pathogenic variants disrupt cortical development through both loss- and gain-of-function mechanisms. Surprisingly, despite severe phenotypes in humans, Rbmx -deficient mice display only mild cortical abnormalities, a discrepancy likely due to compensation by Rbmxl1 , a retrocopy that arose independently in mice and humans. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, with RBMXL1 buffering the impact of RBMX deficiency. These findings establish retrocopies as functional paralogs safeguarding neurodevelopment, and suggest that functional RBMX retrocopy could contribute to the robustness and evolutionary diversification of mammalian brain.

Authors 50

1. Pierre Tilliole

   Institut de génétique et de biologie moléculaire et cellulaire

   Affiliation as printed

   IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

   IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

2. Carolin Mattausch

   Essen University Hospital · University of Duisburg-Essen

   Affiliation as printed

   Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen;

   Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen

3. Peggy Tilly

   Institut de génétique et de biologie moléculaire et cellulaire

   Affiliation as printed

   IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

   IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

4. Elsa Leitão

   Essen University Hospital · University of Duisburg-Essen

   Affiliation as printed

   Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen

5. Lucile Boutaud

   Hôpital Necker-Enfants Malades · Assistance Publique – Hôpitaux de Paris

   Affiliation as printed

   Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades;

   Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades

6. Daphné Lehalle

   Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

   Affiliation as printed

   Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

   Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

7. Isabelle Gourfinkel‐An

   Sorbonne Université · Assistance Publique – Hôpitaux de Paris

   Affiliation as printed

   Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de Neurologie, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

   Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de Neurologie, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

8. Emanuela Argilli

   University of California System

   Affiliation as printed

   Department of Neurology, University of California;

   Department of Neurology, University of California

9. Sharon A. Aufox

   Lurie Children's Hospital

   Affiliation as printed

   Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago;

   Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago

10. Bert Louis Callewaert

    Ghent University

    Affiliation as printed

    Department of Biomolecular Medicine, Ghent University;

    Department of Biomolecular Medicine, Ghent University

11. Perrine Charles

    Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

12. Jessica K. Cinkornpumin

    McGill University

    Affiliation as printed

    Department of Biochemistry, McGill University;

    Department of Biochemistry, McGill University

13. Thomas Courtin

    Hôpital Necker-Enfants Malades · Assistance Publique – Hôpitaux de Paris

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades;

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades

14. Marco Dalla Vecchia

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

15. Erica E. Davis

    Lurie Children's Hospital

    Affiliation as printed

    Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago;

    Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago

16. Boyan Ivanov Dimitrov

    Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel

    Affiliation as printed

    Department of Medical Genetics, University Hospital Brussels (VUB);

    Department of Medical Genetics, University Hospital Brussels (VUB)

17. William B. Dobyns

    University of Minnesota

    Affiliation as printed

    Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota;

    Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota

18. Ekaterina A. Epifanova

    University of Liège

    Affiliation as printed

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman;

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman

19. Erwan Grandgirard

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

20. Matthieu Jung

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

21. Sarah Jurgensmeyer

    Northwestern University

    Affiliation as printed

    Department of Pediatrics, Northwestern University Feinberg School of Medicine;

    Department of Pediatrics, Northwestern University Feinberg School of Medicine

22. Sabine Kaya

    Essen University Hospital · University of Duisburg-Essen

    Affiliation as printed

    Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen;

    Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen

23. Boris Keren

    Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

24. Tahir Naeem Khan

    Lurie Children's Hospital

    Affiliation as printed

    Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago;

    Stanley Manne Children?s Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago

25. Élodie Lejeune

    Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

26. Mingfeng Li

    Yale University

    Affiliation as printed

    Department of Neuroscience, Yale School of Medicine;

    Department of Neuroscience, Yale School of Medicine

27. Yannick Marie

    Centre National de la Recherche Scientifique · Inserm · Institut du Cerveau

    Affiliation as printed

    Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, H&ocircpital de la Piti&eacute Salp&ecirctri&egravre;

    Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, H&ocircpital de la Piti&eacute Salp&ecirctri&egravre

28. Bastien Morlet

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

29. Caroline Nava

    Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre;

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

30. William A. Pastor

    McGill University

    Affiliation as printed

    Department of Biochemistry, McGill University;

    Department of Biochemistry, McGill University

31. Damien Plassard

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

32. Carlos Enrique Prada

    Northwestern University

    Affiliation as printed

    Department of Pediatrics, Northwestern University Feinberg School of Medicine;

    Department of Pediatrics, Northwestern University Feinberg School of Medicine

33. Agnès Rastetter

    Centre National de la Recherche Scientifique · Inserm · Institut du Cerveau

    Affiliation as printed

    Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, H&ocircpital de la Piti&eacute Salp&ecirctri&egravre;

    Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, H&ocircpital de la Piti&eacute Salp&ecirctri&egravre

34. Noémie Schwaller

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

35. Nenad Šestan

    Yale University

    Affiliation as printed

    Department of Neuroscience, Yale School of Medicine;

    Department of Neuroscience, Yale School of Medicine

36. Elliott H. Sherr

    University of California System

    Affiliation as printed

    Department of Neurology, University of California;

    Department of Neurology, University of California

37. Suzanna L. Temple

    Liverpool Hospital

    Affiliation as printed

    Department of Clinical Genetics, Liverpool Hospital;

    Department of Clinical Genetics, Liverpool Hospital

38. Jude-Felix Tenywa

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

39. Sylvia Tielens

    University of Liège

    Affiliation as printed

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman;

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman

40. Arie van Haeringen Aachen Department of Clinical Genetics

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Genetics, Leiden University Medical Center (LUMC);

    Department of Clinical Genetics, Leiden University Medical Center (LUMC)

41. Helen Whitley

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

42. Laurent Nguyen

    University of Liège

    Affiliation as printed

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman;

    Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Li&egravge, CHU Sart Tilman

43. Muriel Rhinn

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire

44. Stephan C. Collins

    Inserm

    Affiliation as printed

    Universit&eacute Bourgogne Europe, INSERM Research Center U1231

45. Delphine Héron

    Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Pitié-Salpêtrière Hospital

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP) Sorbonne Universit&eacute, D&eacutepartement de G&eacuten&eacutetique, H&ocircpital Piti&eacute-Salp&ecirctri&egravre

46. Valérie Cormier‐Daire

    Hôpital Necker-Enfants Malades · Assistance Publique – Hôpitaux de Paris

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades;

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades

47. Tania Attié‐Bitach

    Hôpital Necker-Enfants Malades · Assistance Publique – Hôpitaux de Paris

    Affiliation as printed

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades;

    Assistance Publique- H&ocircpitaux de Paris (APHP), Service de M&eacutedecine G&eacutenomique des Maladies Rares, H&ocircpital Necker-Enfants malades

48. Binnaz Yalcin

    Inserm

    Affiliation as printed

    Universit&eacute Bourgogne Europe, INSERM Research Center U1231

49. Christel Depienne

    Essen University Hospital · University of Duisburg-Essen

    Affiliation as printed

    Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen;

    Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen

50. Juliette D. Godin corresponding

    Institut de génétique et de biologie moléculaire et cellulaire

    Affiliation as printed

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire;

    IGBMC, Institut de G&eacutn&eacuttique et de Biologie Mol&eacutculaire et Cellulaire