De novo missense variants in FBXO11 alter its protein expression and subcellular localization.
| Title: | De novo missense variants in FBXO11 alter its protein expression and subcellular localization. |
|---|---|
| Authors: | 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 EMC; Haack TB; Bertoli M; Hoffjan S; Falb R; Shinawi M; Sticht H; Zweier C |
| Source: | Human molecular genetics [Hum Mol Genet] 2022 Feb 03; Vol. 31 (3), pp. 440-454. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992- |
| MeSH Terms: | F-Box Proteins*/genetics ; Intellectual Disability*/genetics ; Neurodevelopmental Disorders*/genetics; Mutation, Missense/genetics ; Protein-Arginine N-Methyltransferases/genetics ; HEK293 Cells ; HeLa Cells ; Humans |
| 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.; (© The Author(s) 2021. Published by Oxford University Press.) |
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| Grant Information: | UM1 HG008900 United States HG NHGRI NIH HHS; R01 HG009141 United States HG NHGRI NIH HHS; United Kingdom WT_ Wellcome Trust |
| Substance Nomenclature: | 0 (F-Box Proteins); EC 2.1.1.319 (FBXO11 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases) |
| Entry Date(s): | Date Created: 20210910 Date Completed: 20220427 Latest Revision: 20220531 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8825234 |
| DOI: | 10.1093/hmg/ddab265 |
| PMID: | 34505148 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't