TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome

Elizabeth A. Werren, Geneva R. LaForce, Anshika Srivastava, Delia R. Perillo, Shaokun Li, Katherine Johnson, Safa Baris, Brandon Berger, Samantha L. Regan, Christian D. Pfennig, Sonja Munnik, Rolph Pfundt, Malavika Hebbar, Raúl Jimenez-Heredia, Elif Karakoc-Aydiner, Ahmet Ozen, Jasmin Dmytrus, Ana Krolo, Ken Corning, E. J. Prijoles, Raymond J. Louie, Robert Roger Lebel, Thuy-Linh Le, Jeanne Amiel, Christopher T. Gordon, Kaan Boztug, Katta M. Girisha, Anju Shukla, Stephanie L. Bielas () and Ashleigh E. Schaffer ()
Additional contact information
Elizabeth A. Werren: University of Michigan Medical School
Geneva R. LaForce: Case Western Reserve University School of Medicine
Anshika Srivastava: University of Michigan Medical School
Delia R. Perillo: University of Michigan Medical School
Shaokun Li: The Jackson Laboratory for Genomic Medicine
Katherine Johnson: The Jackson Laboratory for Genomic Medicine
Safa Baris: Marmara University, Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, The Isil Berat Barlan Center for Translational Medicine
Brandon Berger: The Jackson Laboratory for Genomic Medicine
Samantha L. Regan: University of Michigan Medical School
Christian D. Pfennig: University of Michigan Medical School
Sonja Munnik: Radboud University Medical Centre Nijmegen
Rolph Pfundt: Radboud University Medical Centre Nijmegen
Malavika Hebbar: University of Washington
Raúl Jimenez-Heredia: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Elif Karakoc-Aydiner: Marmara University, Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, The Isil Berat Barlan Center for Translational Medicine
Ahmet Ozen: Marmara University, Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, The Isil Berat Barlan Center for Translational Medicine
Jasmin Dmytrus: Research Centre for Molecular Medicine of the Austrian Academy of Sciences
Ana Krolo: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Ken Corning: Greenwood Genetic Center
E. J. Prijoles: Greenwood Genetic Center
Raymond J. Louie: Greenwood Genetic Center
Robert Roger Lebel: SUNY Upstate Medical University
Thuy-Linh Le: Paris Cité University
Jeanne Amiel: Paris Cité University
Christopher T. Gordon: Paris Cité University
Kaan Boztug: Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Katta M. Girisha: Manipal, Manipal Academy of Higher Education
Anju Shukla: Manipal, Manipal Academy of Higher Education
Stephanie L. Bielas: University of Michigan Medical School
Ashleigh E. Schaffer: Case Western Reserve University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating impaired TREX tetramer formation. Defects in RNA nuclear export functions were not detected in biallelic THOC6 LOF human neural cells. Instead, mis-splicing was detected in human and mouse neural tissue, revealing novel THOC6-mediated TREX coordination of mRNA processing. We demonstrate that THOC6 is required for key signaling pathways known to regulate the transition from proliferative to neurogenic divisions during human corticogenesis. Together, these findings implicate altered RNA processing in the developmental biology of TIDS neuropathology.

Date: 2024
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DOI: 10.1038/s41467-024-45948-y

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