Heterozygous Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization

Authors

Taimoor I. Sheikh, Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
Ricardo Harripaul, Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
Nasim Vasli, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Majid Ghadami, Department of Educational Sciences, Farhangian University, Tehran 19989-63341, Iran.
Susan L. Santangelo, Center for Psychiatric Research, Maine Medical Center Research Institute, Portland, ME 04101, USA.
Muhammad Ayub, Department of Psychiatry, Queen's University, Kingston, ON K7L 7X3, Canada.
Roksana Sasanfar, Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA.
John B. Vincent, Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.

Document Type

Article

Publication Date

12-24-2021

Journal Title

Genes

MeSH Headings

Autism Spectrum Disorder (genetics, pathology); Cell Nucleolus (metabolism); HEK293 Cells; Heterozygote; Humans; Male; Mutation; Phosphoproteins (genetics); RNA-Binding Proteins (genetics)

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 frameshifting indel mutation of , 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 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 -related ASD and other neurodevelopmental phenotypes.

Recommended Citation

Sheikh TI, Harripaul R, Vasli N, Ghadami M, Santangelo SL, Ayub M, Sasanfar R, Vincent JB. Heterozygous De Novo Truncating Mutation of Nucleolin in an ASD Individual Disrupts Its Nucleolar Localization. Genes (Basel). 2021 Dec 24;13(1):51. doi: 10.3390/genes13010051. PMID: 35052391; PMCID: PMC8774667.