Sheikh, TI;
Harripaul, R;
Vasli, N;
Ghadami, M;
Santangelo, SL;
Ayub, M;
Sasanfar, R;
(2022)
Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization.
Genes
, 13
(1)
, Article 51. 10.3390/genes13010051.
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Abstract
Nucleolin (NCL/C23; OMIM: 164035) is a major nucleolar protein that plays a critical role in multiple processes, including ribosome assembly and maturation, chromatin decondensation, and pre-rRNA transcription. Due to its diverse functions, nucleolin has frequently been implicated in pathological processes, including cancer and viral infection. We recently identified a de novo frameshifting indel mutation of NCL, p.Gly664Glufs*70, through whole-exome sequencing of autism spectrum disorder trios. Through the transfection of constructs encoding either a wild-type human nucleolin or a mutant nucleolin with the same C-terminal sequence predicted for the autism proband, and by using co-localization with the nucleophosmin (NPM; B23) protein, we have shown that the nucleolin mutation leads to mislocalization of the NCL protein from the nucleolus to the nucleoplasm. Moreover, a construct with a nonsense mutation at the same residue, p.Gly664*, shows a very similar effect on the location of the NCL protein, thus confirming the presence of a predicted nucleolar location signal in this region of the NCL protein. Real-time fluorescence recovery experiments show significant changes in the kinetics and mobility of mutant NCL protein in the nucleoplasm of HEK293Tcells. Several other studies also report de novo NCL mutations in ASD or neurodevelopmental disorders. The altered mislocalization and dynamics of mutant NCL (p.G664Glufs*70/p.G664*) may have relevance to the etiopathlogy of NCL-related ASD and other neurodevelopmental phenotypes.
| Type: | Article |
|---|---|
| Title: | Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization |
| Location: | Switzerland |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/genes13010051 |
| Publisher version: | http://dx.doi.org/10.3390/genes13010051 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | C23, GAR domain, autism spectrum disorder (ASD), nucleolar localization signal, nucleolin, Autism Spectrum Disorder, Cell Nucleolus, HEK293 Cells, Heterozygote, Humans, Male, Mutation, Phosphoproteins, RNA-Binding Proteins, Nucleolin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health Neuroscience |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10184862 |
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