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Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism

Molecular Psychiatry volume 20, pages 1132–1138 (2015)Cite this article

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Abstract

PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Ptenm3m4 murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

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Acknowledgements

This work was made possible by the Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1 RR024989 provided by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health and a grant from the National Cancer Institute R01CA118980. We also wish to acknowledge the important contribution of the participants and their families.

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Authors and Affiliations

  1. Center for Autism, Pediatric Institute, The Cleveland Clinic, Cleveland, OH, USA,

    T W Frazier & R Embacher

  2. Genomic Medicine Institute, The Cleveland Clinic, Cleveland, OH, USA,

    T W Frazier, A K Tilot, J Mester & C Eng

  3. Neurological Institute, Cleveland Clinic, Cleveland, OH, USA,

    K Koenig

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  1. T W Frazier
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Correspondence to T W Frazier.

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Competing interests

Dr Frazier has received federal funding or research support from, acted as a consultant to, received travel support from and/or received a speaker’s honorarium from the Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Shire Development, Bristol-Myers Squibb, National Institutes of Health and the Brain and Behavior Research Foundation. Dr Eng has received research support from IntegraGen, was a Doris Duke Distinguished Clinical Scientist, holds the Sondra J and Stephen R Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and is an ACS Clinical Research Professor.

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Frazier, T., Embacher, R., Tilot, A. et al. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol Psychiatry 20, 1132–1138 (2015). https://doi.org/10.1038/mp.2014.125

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