TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Lindsey D. Goodman, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Heidi Cope, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Zelha Nil, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Thomas A. Ravenscroft, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Wu-Lin Charng, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Shenzhao Lu, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
An-Chi Tien, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Rolph Pfundt, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, PO Box 9101, Nijmegen, the Netherlands.
David A. Koolen, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, PO Box 9101, Nijmegen, the Netherlands.
Charlotte A. Haaxma, Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Geert Grooteplein Zuid 10, 6525 GA, PO Box 9101, the Netherlands.
Hermine E. Veenstra-Knol, Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
Jolien S. Wassink-Ruiter, Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
Marijke R. Wevers, Department of Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Melissa Jones, Houston Area Pediatric Neurology, 24514 Kingsland Blvd, Katy, TX 77494, USA.
Laurence E. Walsh, Department of Pediatric Neurology, Riley Hospital for Children, Indianapolis, IN 46202, USA.
Victoria H. Klee, Department of Pediatric Neurology, Riley Hospital for Children, Indianapolis, IN 46202, USA.
Miel Theunis, Center for Human Genetics, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium.
Eric Legius, Department of Human Genetics, University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
Dora Steel, Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Katy E. Barwick, Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
Manju A. Kurian, Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK; Department of Neurology, Great Ormond Street Hospital, London WC1N 3JH, UK.
Shekeeb S. Mohammad, T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Westmead, NSW 2145, Australia.
Russell C. Dale, T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Westmead, NSW 2145, Australia.
Paulien A. Terhal, Department of Genetics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
Ellen van Binsbergen, Department of Genetics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
Brian Kirmse, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Bethany Robinette, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Benjamin Cogné, Centre hospitalier universitaire (CHU) de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France; INSERM, CNRS, UNIV Nantes, Centre hospitalier universitaire (CHU) de Nantes, l'institut du thorax, 44007 Nantes, France.
Bertrand Isidor, Centre hospitalier universitaire (CHU) de Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093 Nantes, France; INSERM, CNRS, UNIV Nantes, Centre hospitalier universitaire (CHU) de Nantes, l'institut du thorax, 44007 Nantes, France.
Theresa A. Grebe, Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Department of Child Health, University of Arizona College of Medicine Phoenix, Phoenix, AZ 85004, USA.
Peggy Kulch, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
Bryan E. Hainline, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Document Type

Article

Abstract

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

Keywords

Drosophila, Importin-3, Karyopherin-β2b, TNPO1, TNPO2, Transportin, global developmental delays, intellectual disability, nucleocytoplasmic shuttling, rare disease

Medical Subject Headings

Alleles; Amino Acid Sequence; Animals; Developmental Disabilities (genetics, metabolism, pathology); Drosophila Proteins (antagonists & inhibitors, genetics, metabolism); Drosophila melanogaster (genetics, growth & development, metabolism); Eye Diseases, Hereditary (genetics, metabolism, pathology); Female; Gene Dosage; Gene Expression Regulation, Developmental; Genome, Human; Humans; Infant; Infant, Newborn; Intellectual Disability (genetics, metabolism, pathology); Karyopherins (antagonists & inhibitors, genetics, metabolism); Male; Musculoskeletal Abnormalities (genetics, metabolism, pathology); Mutation; Neurons (metabolism, pathology); RNA, Small Interfering (genetics, metabolism); Sequence Alignment; Sequence Homology, Amino Acid; Whole Genome Sequencing; beta Karyopherins (genetics, metabolism); ran GTP-Binding Protein (genetics, metabolism)

Publication Date

9-2-2021

Publication Title

American journal of human genetics

E-ISSN

1537-6605

Volume

108

Issue

9

First Page

1669

Last Page

1691

PubMed ID

34314705

Digital Object Identifier (DOI)

10.1016/j.ajhg.2021.06.019

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