N-terminal Variant Asp14Asn of the Human p70 S6 Kinase 1 Enhances Translational Signaling Causing Different Effects in Developing and Mature Neuronal Cells

Venkatasubramani, J.P., Subramanyam, P., Pal, R., Reddy, B.K., Srinivasan, D.J., Chattarji, S., Iossifov, I., Klann, E., Bhattacharya, S. (March 2020) N-terminal Variant Asp14Asn of the Human p70 S6 Kinase 1 Enhances Translational Signaling Causing Different Effects in Developing and Mature Neuronal Cells. Neurobiology of Learning and Memory, 171 (107203). ISSN 1074-7427

Abstract

The ribosomal p70 S6 Kinase 1 (S6K1) has been implicated in the etiology of complex neurological diseases including autism, depression and dementia. Though no major gene disruption has been reported in humans in RPS6KB1, single nucleotide variants (SNVs) causing missense mutations have been identified, which have not been assessed for their impact on protein function. These S6K1 mutations have the potential to influence disease progression and treatment response. We mined the Simon Simplex Collection (SSC) and SPARK autism database to find inherited SNVs in S6K1 and characterized the effect of two missense SNVs, Asp14Asn (allele frequency = 0.03282%) and Glu44Gln (allele frequency = 0.0008244%), on S6K1 function in HEK293, human ES cells and primary neurons. Expressing Asp14Asn in HEK293 cells resulted in increased basal phosphorylation of downstream targets of S6K1 and increased de novo translation. This variant also showed blunted response to the specific S6K1 inhibitor, FS-115. In human embryonic cell line Shef4, Asp14Asn enhanced spontaneous neural fate specification in the absence of differentiating growth factors. In addition to enhanced translation, neurons expressing Asp14Asn exhibited impaired dendritic arborization and increased levels of phosphorylated ERK 1/2. Finally, in the SSC families tracked, Asp14Asn segregated with lower IQ scores when found in the autistic individual rather than the unaffected sibling. The Glu44Gln mutation showed a milder, but opposite phenotype in HEK cells as compared to Asp14Asn. Although the Glu44Gln mutation displayed increased neuronal translation, it had no impact on neuronal morphology. Our results provide the first characterization of naturally occurring human S6K1 variants on cognitive phenotype, neuronal morphology and maturation, underscoring again the importance of translation control in neural development and plasticity.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders > mental disorders > delirium dementia cognitive disorders diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > mental disorders diseases & disorders > mental disorders > personality disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > alleles organism description > animal diseases & disorders > mental disorders > personality disorders > autism organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function organs, tissues, organelles, cell types and functions > tissues types and functions > hippocampus organism description > animal > mammal bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > neurogenesis organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent > rat organs, tissues, organelles, cell types and functions > organelles, types and functions > ribosome organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > single nucleotide polymorphism organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Iossifov, Ivan
Communities:	CSHL labs > Iossifov lab
Depositing User:	Adrian Gomez
Date:	5 March 2020
Date Deposited:	02 Apr 2020 19:12
Last Modified:	01 Feb 2024 19:10
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/39219

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