Journal article
Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization
Genes, v 13(1), 51
24 Dec 2021
PMID: 35052391
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization
- Creators
- Taimoor I. Sheikh - Drexel University, Pathology (and Laboratory Medicine)Ricardo Harripaul - University of TorontoNasim Vasli - Hospital for Sick ChildrenMajid Ghadami - Farhangian UniversitySusan L. Santangelo - Harvard UniversityMuhammad Ayub - Queen's UniversityRoksana Sasanfar - Harvard UniversityJohn B. Vincent - University of Toronto
- Publication Details
- Genes, v 13(1), 51
- Publisher
- MDPI
- Number of pages
- 10
- Grant note
- University of Toronto open fellowship; University of Toronto PJT-156402 / Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) Dalton Whitebread Scholarship Fund Peterborough K.M. Hunter Charitable Foundation Graduate Scholarship NARSAD Young Investigator Award; NARSAD Margaret and Howard Gamble Research Grant
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pathology (and Laboratory Medicine)
- Web of Science ID
- WOS:000758904800001
- Scopus ID
- 2-s2.0-85122021433
- Other Identifier
- 991022093054304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity