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Author Notes:

Correspondence: christina.gross@cchmc.org

ACP performed the S6 and phospho-S6 ELISAs, conducted most of the Western blots and PI3K activity assays, analyzed the experiments, and revised the manuscript.

LMS performed and analyzed the protein synthesis studies and revised the manuscript.

PSH performed the statistical analyses and revised the manuscript.

GJB contributed to the study design and interpretation of results and revised the manuscript.

CG contributed to the study design and interpretation of the study, coordinated and analyzed the experiments, and drafted the manuscript.

We are grateful to the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC), and we gratefully acknowledge the resources provided by the Autism Genetic Resource Exchange (AGRE) Consortium and the participating AGRE families.

The authors thank Michelle Degutis and Lian Li for technical assistance and Dr. Christa L. Martin and Dr. Stephen T. Warren for helpful discussions.

The authors declare that they have no competing interests.


Research Funding:

The AGRE is a program of Autism Speaks and is supported, in part, by grant 1U24MH081810 from the National Institute of Mental Health to Clara M. Lajonchere (PI).This research was supported by an SFARI Pilot Grant (CG and GB), a Trailblazer Award (GB) and a Pilot Grant (CG) from Autism Speaks, and a NARSAD Young Investigator Award (CG) and a NARSAD Distinguished Investigator Award (GB) from the Brain and Behavior Research Foundation.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Neurosciences
  • Neurosciences & Neurology
  • PI3K/mTOR signaling
  • p110 delta
  • Autism
  • Biomarker
  • S6 phosphorylation
  • IC87114
  • MTOR

Increased expression of the PI3K catalytic subunit p110 delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family

Journal Title:

Molecular Autism


Volume 7, Number 1


, Pages 3-3

Type of Work:

Article | Final Publisher PDF


Background: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. Methods: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. Results: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110δ, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110δ-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. Conclusions: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110δ as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110δ activity was recently associated with schizophrenia, and our results suggest that p110δ may also be implicated in autism.

Copyright information:

© Poopal et al. 2016

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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