TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila
| Autor: | David A. Koolen, Yue Si, Benjamin Cogné, Pamela Trapane, Eric W. Klee, Manju A. Kurian, Miel Theunis, Eva Morava, Shekeeb S. Mohammad, Oguz Kanca, Matthew J. Moulton, Paulien A Terhal, Peggy Kulch, Queenie K.-G. Tan, An-Chi Tien, Shenzhao Lu, Erica L. Macke, Hugo J. Bellen, Katy Barwick, Bryan E. Hainline, Russell C. Dale, Lindsey D. Goodman, Katherine Sapp, Hermine E. Veenstra-Knol, Eric Legius, Amber Begtrup, Dora Steel, D. Dutta, Victoria H. Klee, Christopher J. Spencer, Bethany Robinette, Ellen van Binsbergen, Michael F. Wangler, Laurence E. Walsh, Shinya Yamamoto, Thomas A. Ravenscroft, Brian Kirmse, Bertrand Isidor, Marijke R. Wevers, Zelha Nil, Heidi Cope, Theresa A. Grebe, Melissa Jones, Wu Lin Charng, Rolph Pfundt, Jolien S. Klein Wassink-Ruiter, Charlotte A. Haaxma |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Developmental Disabilities Gene Dosage DE-NOVO medicine.disease_cause NUCLEAR-IMPORT Drosophila Proteins Global developmental delay RNA Small Interfering Genetics (clinical) Neurons Genetics Mutation Gene Expression Regulation Developmental Eye Diseases Hereditary GAL4 SYSTEM Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] beta Karyopherins Phenotype Drosophila melanogaster Essential gene Female Beta Karyopherins Drosophila Protein Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] EXPRESSION C-FOS PROTEINS Karyopherins Biology Article All institutes and research themes of the Radboud University Medical Center Intellectual Disability medicine Animals Humans Amino Acid Sequence Alleles Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] COMPLEX Sequence Homology Amino Acid Whole Genome Sequencing Genome Human MUTATIONS Infant Newborn Infant biology.organism_classification MUSHROOM BODY TRANSPORTIN Musculoskeletal Abnormalities ran GTP-Binding Protein Ectopic expression Sequence Alignment |
| Zdroj: | Am J Hum Genet American Journal of Human Genetics, 108(9), 1669-1691. CELL PRESS American Journal of Human Genetics, 108, 9, pp. 1669-1691 American Journal of Human Genetics, 108, 1669-1691 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2021.06.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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