TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila PMID: 34314705

GLP-1 and Obesity Research

2026-08-18

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

Am J Hum Genet. 2021 Sep 2;108(9):1669-1691. doi: 10.1016/j.ajhg.2021.06.019.

Lindsey D Goodman ¹ , Heidi Cope ² , Zelha Nil ¹ , Thomas A Ravenscroft ¹ , Wu-Lin Charng ¹ , Shenzhao Lu ¹ , An-Chi Tien ¹ , Rolph Pfundt ³ , David A Koolen ³ , Charlotte A Haaxma ⁴ , Hermine E Veenstra-Knol ⁵ , Jolien S Klein Wassink-Ruiter ⁵ , Marijke R Wevers ⁶ , Melissa Jones ⁷ , Laurence E Walsh ⁸ , Victoria H Klee ⁸ , Miel Theunis ⁹ , Eric Legius ¹⁰ , Dora Steel ¹¹ , Katy E S Barwick ¹² , Manju A Kurian ¹¹ , Shekeeb S Mohammad ¹³ , Russell C Dale ¹³ , Paulien A Terhal ¹⁴ , Ellen van Binsbergen ¹⁴ , Brian Kirmse ¹⁵ , Bethany Robinette ¹⁵ , Benjamin Cogné ¹⁶ , Bertrand Isidor ¹⁶ , Theresa A Grebe ¹⁷ , Peggy Kulch ¹⁸ , Bryan E Hainline ¹⁹ , Katherine Sapp ¹⁹ , Eva Morava ²⁰ , Eric W Klee ²⁰ , Erica L Macke ²¹ , Pamela Trapane ²² , Christopher Spencer ²² , Yue Si ²³ , Amber Begtrup ²³ , Matthew J Moulton ¹ , Debdeep Dutta ¹ , Oguz Kanca ¹ , Undiagnosed Diseases Network ²⁴ , Michael F Wangler ¹ , Shinya Yamamoto ²⁵ , Hugo J Bellen ²⁶ , Queenie K-G Tan ²⁷

Affiliations

1. 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.
2. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
3. 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.
4. Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Geert Grooteplein Zuid 10, 6525 GA, PO Box 9101, the Netherlands.
5. Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
6. Department of Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
7. Houston Area Pediatric Neurology, 24514 Kingsland Blvd, Katy, TX 77494, USA.
8. Department of Pediatric Neurology, Riley Hospital for Children, Indianapolis, IN 46202, USA.
9. Center for Human Genetics, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium.
10. Department of Human Genetics, University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
11. 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.
12. Molecular Neurosciences, Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK.
13. 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.
14. Department of Genetics, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands.
15. Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
16. 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.
17. Phoenix Children's Hospital, Phoenix, AZ 85016, USA; Department of Child Health, University of Arizona College of Medicine Phoenix, Phoenix, AZ 85004, USA.
18. Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
19. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
20. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
21. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
22. University of Florida, College of Medicine, Jacksonville, Jacksonville, FL 32209, USA.
23. GeneDx, Gaithersburg, MD 20877, USA.
24. The Undiagnosed Diseases Network (UDN) consortia, see Supplemental Note S2 for co-investigators, Harvard University, Cambridge, MA 02138, USA.
25. 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; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
26. 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; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
27. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: [email protected].

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.