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

Frazier, T., Embacher, R., Tilot, A. K., Koenig, K., Mester, J., & Eng, C. (2015). Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Molecular Psychiatry., 20, 1132-1138. doi:10.1038/mp.2014.125.

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Frazier_etal_2015_MolPsy.pdf (Verlagsversion), 392KB
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Frazier, TW1, Autor
Embacher, R2, Autor
Tilot, Amanda K.3, Autor           
Koenig, K3, Autor
Mester, J4, Autor
Eng, C3, Autor
Affiliations:
1 Center for Autism, Pediatric Institute, The Cleveland Clinic, Cleveland, OH, USA [2] Genomic Medicine Institute, The Cleveland Clinic, Cleveland, OH, USA., ou_persistent22              
2Center for Autism, Pediatric Institute, The Cleveland Clinic, Cleveland, OH, USA, ou_persistent22              
3Genomic Medicine Institute, The Cleveland Clinic, Cleveland, OH, USA., ou_persistent22              
4Neurological Institute, Cleveland Clinic, Cleveland, OH, USA, ou_persistent22              

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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2014-08-282014-10-072015
 Publikationsstatus: Erschienen
 Seiten: 7
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1038/mp.2014.125
 Art des Abschluß: -

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Titel: Molecular Psychiatry.
Genre der Quelle: Zeitschrift
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Seiten: - Band / Heft: 20 Artikelnummer: - Start- / Endseite: 1132 - 1138 Identifikator: ISSN: 1359-4184
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131