Frontiers in Molecular Neuroscience (Feb 2020)
Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor
- Raman Kumar,
- Elizabeth Palmer,
- Elizabeth Palmer,
- Alison E. Gardner,
- Renee Carroll,
- Siddharth Banka,
- Siddharth Banka,
- Ola Abdelhadi,
- Dian Donnai,
- Dian Donnai,
- Ype Elgersma,
- Ype Elgersma,
- Cynthia J. Curry,
- Alice Gardham,
- Mohnish Suri,
- Rishikesh Malla,
- Lauren Ilana Brady,
- Mark Tarnopolsky,
- Dimitar N. Azmanov,
- Dimitar N. Azmanov,
- Vanessa Atkinson,
- Vanessa Atkinson,
- Michael Black,
- Michael Black,
- Gareth Baynam,
- Lauren Dreyer,
- Lauren Dreyer,
- Robin Z. Hayeems,
- Christian R. Marshall,
- Gregory Costain,
- Marja W. Wessels,
- Julia Baptista,
- James Drummond,
- Melanie Leffler,
- Michael Field,
- Jozef Gecz,
- Jozef Gecz
Affiliations
- Raman Kumar
- Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- Elizabeth Palmer
- Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia
- Elizabeth Palmer
- School of Women’s and Children’s Health, University of New South Wales, Randwick, NSW, Australia
- Alison E. Gardner
- Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- Renee Carroll
- Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- Siddharth Banka
- Faculty of Biology, Medicine and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
- Siddharth Banka
- Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom
- Ola Abdelhadi
- Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom
- Dian Donnai
- Faculty of Biology, Medicine and Health, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
- Dian Donnai
- Manchester Centre for Genomic Medicine, St. Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom
- Ype Elgersma
- Department of Neuroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Ype Elgersma
- ENCORE Expertise Centre for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Cynthia J. Curry
- Genetic Medicine, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
- Alice Gardham
- North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, United Kingdom
- Mohnish Suri
- 0Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, and the 100,000 Genomes Project and the Genomics England Research Consortium, Nottingham, United Kingdom
- Rishikesh Malla
- 1Division of Pediatric Neurology, Medical University of South Carolina, Charleston, SC, United States
- Lauren Ilana Brady
- 2Department of Pediatrics, McMaster University Medical Centre, Hamilton, ON, Canada
- Mark Tarnopolsky
- 2Department of Pediatrics, McMaster University Medical Centre, Hamilton, ON, Canada
- Dimitar N. Azmanov
- 3Department of Diagnostic Genomics, PathWest, Nedlands, WA, Australia
- Dimitar N. Azmanov
- 4Division of Pathology and Laboratory Medicine, Medical School, University of Western Australia, Crawley, WA, Australia
- Vanessa Atkinson
- 3Department of Diagnostic Genomics, PathWest, Nedlands, WA, Australia
- Vanessa Atkinson
- 4Division of Pathology and Laboratory Medicine, Medical School, University of Western Australia, Crawley, WA, Australia
- Michael Black
- 3Department of Diagnostic Genomics, PathWest, Nedlands, WA, Australia
- Michael Black
- 4Division of Pathology and Laboratory Medicine, Medical School, University of Western Australia, Crawley, WA, Australia
- Gareth Baynam
- 5Faculty of Health and Medical Sciences, University of Western Australia Medical School, Perth, WA, Australia
- Lauren Dreyer
- 6Genetic Services of Western Australia, Undiagnosed Diseases Program, Department of Health, Government of Western Australia, Perth, WA, Australia
- Lauren Dreyer
- 7Linear Clinical Research, Perth, WA, Australia
- Robin Z. Hayeems
- 8Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, and Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada
- Christian R. Marshall
- 9Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Gregory Costain
- 0Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada
- Marja W. Wessels
- 1Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
- Julia Baptista
- 2Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
- James Drummond
- 3Neuroradiology, Royal North Shore Hospital, Sydney, NSW, Australia
- Melanie Leffler
- Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia
- Michael Field
- Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia
- Jozef Gecz
- Adelaide Medical School and the Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
- Jozef Gecz
- 4Childhood Disability Prevention, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- DOI
- https://doi.org/10.3389/fnmol.2020.00012
- Journal volume & issue
-
Vol. 13
Abstract
Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals’ has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.
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