De novo missense variants in FBXO11 alter its protein expression and subcellular localization

Gregor A, Meerbrei T, Gerstner T, Toutain A, Lynch SA, Stals K, Maxton C, Lemke JR, Bernat JA, Bombei HM, Foulds N, Hunt D, Kuechler A, Beygo J, Stöbe P, Bouman A, Palomares-Bralo M, Santos-Simarro F, Garcia-Minaur S, Pacio-Miguez M, Popp B, Vasileiou G, Hebebrand M, Reis A, Schuhmann S, Krumbiegel M, Brown NJ, Sparber P, Melikyan L, Bessonova L, Cherevatova T, Sharkov A, Shcherbakova N, Dabir T, Kini U, Schwaibold EM, Haack TB, Bertoli M, Hoffjan S, Falb R, Shinawi M, Sticht H, Zweier C (2022)

Publication Type: Journal article, Original article

Publication year: 2022

Journal

Book Volume: 31

Pages Range: 440-454

Journal Issue: 3

DOI: 10.1093/hmg/ddab265

Abstract

Recently, others and we identified de novo FBXO11 (F-Box only protein 11) 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.

Authors with CRIS profile

Involved external institutions

University of Iowa Hospitals and Clinics (UIHC) United States (USA) (US) Hospital Universitario La Paz Spain (ES) The University of Melbourne Australia (AU) Research Centre for Medical Genetics Russian Federation (RU) Pirogov Russian National Research Medical University (RSMU / RNRMU) Russian Federation (RU) Eberhard Karls Universität Tübingen Germany (DE) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) University Hospital Southampton NHS United Kingdom (GB) Newcastle upon Tyne Hospitals NHS Foundation Trust United Kingdom (GB) Oxford University Hospitals NHS Foundation Trust United Kingdom (GB) Universitätsklinikum Essen Germany (DE) Belfast City Hospital / Ospidéal Chathair Bhéal Feirste United Kingdom (GB) Erasmus University Medical Center (MC) Netherlands (NL) Universität Leipzig Germany (DE) Ruhr-Universität Bochum (RUB) Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Sørlandet Hospital Kristiansand Norway (NO) Washington University in St. Louis United States (USA) (US) Temple Street Children's University Hospital / Children's Health Ireland (CHI) Ireland (IE) Centre Hospitalier Régional Universitaire de Tours France (FR)

How to cite

APA:

Gregor, A., Meerbrei, T., Gerstner, T., Toutain, A., Lynch, S.A., Stals, K.,... Zweier, C. (2022). De novo missense variants in FBXO11 alter its protein expression and subcellular localization. Human Molecular Genetics, 31(3), 440-454. https://doi.org/10.1093/hmg/ddab265

MLA:

Gregor, Anne, et al. "De novo missense variants in FBXO11 alter its protein expression and subcellular localization." Human Molecular Genetics 31.3 (2022): 440-454.

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