Journal article
De novo missense variants in FBXO11 alter its protein expression and subcellular localization
Human molecular genetics, Vol.31(3), pp.440-454
09/09/2021
DOI: 10.1093/hmg/ddab265
PMCID: PMC8825234
PMID: 34505148
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.
Details
- Title: Subtitle
- De novo missense variants in FBXO11 alter its protein expression and subcellular localization
- Creators
- Anne Gregor - University Hospital of BernTanja Meerbrei - Friedrich-Alexander-Universität Erlangen-NürnbergThorsten Gerstner - Sørlandet Hospital ArendalAnnick Toutain - Université de ToursSally Ann Lynch - Temple Street Children's University HospitalKaren Stals - Royal Devon & Exeter NHS Foundation TrustCaroline Maxton - Praxis für Kinderneurologie, 22767, Hamburg, Germany.Johannes R Lemke - University Hospital LeipzigJohn A Bernat - University of IowaHannah M Bombei - University of IowaNicola Foulds - University Hospital Southampton NHS Foundation TrustDavid Hunt - University of SouthamptonAlma Kuechler - University of Duisburg-EssenJasmin Beygo - University of Duisburg-EssenPetra Stöbe - Center for Applied GenomicsArjan Bouman - Erasmus MCMaria Palomares-Bralo - , , Madrid 28046Fernando Santos-Simarro - Hospital Universitario La PazSixto Garcia-Minaur - Hospital Universitario La PazMarta Pacio-Miguez - Hospital Universitario La PazBernt Popp - University Hospital LeipzigGeorgia Vasileiou - Friedrich-Alexander-Universität Erlangen-NürnbergMoritz Hebebrand - Friedrich-Alexander-Universität Erlangen-NürnbergAndré Reis - Friedrich-Alexander-Universität Erlangen-NürnbergSarah Schuhmann - Friedrich-Alexander-Universität Erlangen-NürnbergMandy Krumbiegel - Friedrich-Alexander-Universität Erlangen-NürnbergNatasha J Brown - Royal Children's HospitalPeter Sparber - Research Centre for Medical GeneticsLyusya Melikyan - Research Centre for Medical GeneticsLiudmila Bessonova - Research Centre for Medical GeneticsTatiana Cherevatova - Research Centre for Medical GeneticsArtem Sharkov - Pirogov Russian National Research Medical UniversityNatalia Shcherbakova - Pirogov Russian National Research Medical UniversityTabib Dabir - Belfast City HospitalUsha Kini - Oxford University Hospitals NHS TrustEva M C Schwaibold - Heidelberg UniversityTobias B Haack - University of TübingenMarta Bertoli - Newcastle upon Tyne Hospitals NHS Foundation TrustSabine Hoffjan - Ruhr University BochumRuth Falb - University of TübingenMarwan Shinawi - , Department of Pediatrics, , St. Louis, MO 63110Heinrich Sticht - Friedrich-Alexander-Universität Erlangen-NürnbergChristiane Zweier - University Hospital of Bern
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.31(3), pp.440-454
- DOI
- 10.1093/hmg/ddab265
- PMID
- 34505148
- PMCID
- PMC8825234
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Grant note
- ; 837547 / ; P035 / ; R01 HG009141 / ; HICF-1009-003 / ; UM1 HG008900 / ;
- Language
- English
- Date published
- 09/09/2021
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984354153902771
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