De novo missense variants in FBXO11 alter its protein expression and subcellular localization
Creators
- Anne Gregor1
- Tanja Meerbrei2
- Thorsten Gerstner3
- Annick Toutain4
- Sally Ann Lynch5
- Karen Stals6
- Caroline Maxton7
- Johannes R. Lemke8
- John A. Bernat9
- Hannah M. Bombei9
- Nicola Foulds10
- David Hunt11
- Alma Kuechler12
- Jasmin Beygo12
- Petra Stöbe13
- Arjan Bouman14
- Maria Palomares-Bralo15
- Fernando Santos-Simarro15
- Sixto Garcia-Minaur15
- Marta Pacio-Miguez15
- Bernt Popp8
- Georgia Vasileiou2
- Moritz Hebebrand2
- André Reis2
- Sarah Schuhmann2
- Mandy Krumbiegel2
- Natasha J. Brown16
- Peter Sparber17
- Lyusya Melikyan17
- Liudmila Bessonova17
- Tatiana Cherevatova17
- Artem Sharkov18
- Natalia Shcherbakova19
- Tabib Dabir20
- Usha Kini21
- Eva M.C. Schwaibold22
- Tobias B. Haack13
- Marta Bertoli23
- Sabine Hoffjan24
- Ruth Falb13
- Marwan Shinawi25
- Heinrich Sticht26
- Christiane Zweier1
- 1. Department of Human Genetics, Inselspital Bern, University of Bern, 3010 Bern, Switzerland.
- 2. nstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
- 3. Department of Pediatrics, Sørlandet Hospital, 4838 Arendal, Norway.
- 4. Service de Génétique, CHU de Tours, 37044 Tours, France.
- 5. Dept of Clinical Genetics, Temple Street Children's Hospital Dublin 1, D01 YC67, Dublin, Ireland.
- 6. Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust, Exeter, EX2 5DW, UK.
- 7. Praxis für Kinderneurologie, 22767 Hamburg, Germany.
- 8. Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103 Leipzig, Germany.
- 9. Division of Medical Genetics & Genomics, Stead Family Department of Pediatrics, University of Iowa Hospital and Clinics, 52242 Iowa City, IA, USA.
- 10. Weesex Clinical Genetics Services, University Hospital Southampton, Southampton SO16 5YA, UK.
- 11. Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton SO16 5YA, UK.
- 12. Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
- 13. Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
- 14. Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
- 15. Institute of Medical and Molecular Genetics, University Hospital La Paz, 28046 Madrid, Spain.
- 16. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3010, Australia.
- 17. Research Centre for Medical Genetics, Moscow 115522, Russia.
- 18. Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Genomed Ltd., Moscow 117997, Russia.
- 19. Independent Clinical Bioinformatics Laboratory, Moscow 117997, Russia.
- 20. Department of Genetic Medicine, Belfast City Hospital, Belfast, BT9 7AB, Northern Ireland, United Kingdom.
- 21. Oxford Centre for Genomic Medicine, Oxford and Spires Cleft Centre, Oxford OX3 9DU, UK.
- 22. Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany.
- 23. Northern Genetics Service, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, NE1 3BZ, UK.
- 24. Department of Human Genetics, Ruhr University, 44801, Bochum, Germany.
- 25. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
- 26. Institute of Bioichemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Description
Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein.
To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs.
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