title: THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.
abstract: Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Corbett
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Woenig
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Lloyd
authors.initials: L
authors.lastname: Weir
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Douglas
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Friend
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Gardner
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Lachlan A
authors.initials: LA
authors.lastname: Jolly
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia.
authors.forename: Chuan
authors.initials: C
authors.lastname: Tan
authors.affiliation: Monash Genetics, Monash Medical Centre, Clayton, VIC 3168, Australia; Department of Paediatrics, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Hunter
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Palmer
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Leffler
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rogers
authors.affiliation: Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia.
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bienek
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Jensen
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Van Buggenhout
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Magdeburger Strasse 2, 06112 Halle (Saale), Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: INSERM U930, Imaging and Brain, François-Rabelais University, 37000 Tours, France; INSERM U930, Service de Génétique, Centre Hospitalier Régional Universitaire, 37000 Tours, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Harvard Medical School, Harvard University, Boston, MA 02115, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Reed
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; South Australian Clinical Genetics Service, SA Pathology, North Adelaide, SA 5006, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.affiliation: School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, Adelaide, SA 5000, Australia; School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: jozef.gecz@adelaide.edu.au.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D041321:Chromosomes, Human, X / Q000235:genetics*; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C579432:Thoc2 protein, human