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

Human Molecular Genetics (Q1; IF – 6.15) published the results of study by the Functional Genomics Laboratory researchers and the RCMG medical geneticists as part of large-scale international collaboration.

De novo FBXO11 variants were identified as causative for a variable neurodevelopmental disorder (NDD). The study analyzed clinical and molecular genetic information for 23 patients with de novo pathogenic missense variants in the FBXO11 gene. A pronounced clinical heterogeneity in the sample of patients was revealed. The main common clinical symptoms included developmental delay and/or intellectual disability. Behavioral anomalies, muscle hypotonia and various facial dysmorphism were also frequent symptoms.

The mutational spectrum included intragenic deletions and missense variants distributed across the gene structure. A functional analysis of 17 missense variants was performed in the research. The majority of variants were shown to have altered subcellular protein localization and/or reduced expression. The functional data obtained proved the pathogenicity of most missense variants and highlighted haploinsufficiency as the most likely disease mechanism.

Anne Gregor, Tanja Meerbrei, Thorsten Gerstner, Annick Toutain, Sally Ann Lynch, Karen Stals, Caroline Maxton, Johannes R Lemke, John A Bernat, Hannah M Bombei, Nicola Foulds, David Hunt, Alma Kuechler, Jasmin Beygo, Petra Stöbe, Arjan Bouman, Maria Palomares-Bralo, Fernando Santos-Simarro, Sixto Garcia-Minaur, Marta Pacio-Miguez, Bernt Popp, Georgia Vasileiou, Moritz Hebebrand, André Reis, Sarah Schuhmann, Mandy Krumbiegel, Natasha J Brown, Peter Sparber, Lyusya Melikyan, Liudmila Bessonova, Tatiana Cherevatova, Artem Sharkov, Natalia Shcherbakova, Tabib Dabir, Usha Kini, Eva M C Schwaibold, Tobias B Haack, Marta Bertoli, Sabine Hoffjan, Ruth Falb, Marwan Shinawi, Heinrich Sticht, Christiane Zweier, De novo missense variants in FBXO11 alter its protein expression and subcellular localization, Human Molecular Genetics, 2021;, ddab265,