Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism
Abstract Background PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the...
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doaj-d4cdaba4f0274c65bdeb0e800665007f2021-01-31T16:11:23ZengBMCMolecular Autism2040-23922021-01-0112111410.1186/s13229-020-00406-6Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autismThomas W. Frazier0Ritika Jaini1Robyn M. Busch2Matthew Wolf3Tammy Sadler4Patricia Klaas5Antonio Y. Hardan6Julian A. Martinez-Agosto7Mustafa Sahin8Charis Eng9the Developmental Synaptopathies ConsortiumDepartment of Psychology, John Carroll UniversityGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicDepartment of Neurology and Epilepsy Center, Neurological Institute, Cleveland ClinicDepartment of Child Psychiatry and Behavioral Sciences, Stanford University School of MedicineDepartment of Human Genetics, UCLATranslational Neurosciences Center, Department of Neurology, Boston Children’s Hospital and Harvard Medical SchoolGenomic Medicine Institute, Lerner Research Institute, Cleveland ClinicAbstract Background PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. Methods Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. Results Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. Limitations Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. Conclusions Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. Trial registration ClinicalTrials.gov Identifier NCT02461446https://doi.org/10.1186/s13229-020-00406-6PTENProteinMolecularAutism spectrum disorderCognitionBehavior |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thomas W. Frazier Ritika Jaini Robyn M. Busch Matthew Wolf Tammy Sadler Patricia Klaas Antonio Y. Hardan Julian A. Martinez-Agosto Mustafa Sahin Charis Eng the Developmental Synaptopathies Consortium |
spellingShingle |
Thomas W. Frazier Ritika Jaini Robyn M. Busch Matthew Wolf Tammy Sadler Patricia Klaas Antonio Y. Hardan Julian A. Martinez-Agosto Mustafa Sahin Charis Eng the Developmental Synaptopathies Consortium Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism Molecular Autism PTEN Protein Molecular Autism spectrum disorder Cognition Behavior |
author_facet |
Thomas W. Frazier Ritika Jaini Robyn M. Busch Matthew Wolf Tammy Sadler Patricia Klaas Antonio Y. Hardan Julian A. Martinez-Agosto Mustafa Sahin Charis Eng the Developmental Synaptopathies Consortium |
author_sort |
Thomas W. Frazier |
title |
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism |
title_short |
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism |
title_full |
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism |
title_fullStr |
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism |
title_full_unstemmed |
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism |
title_sort |
cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous pten mutations with and without autism |
publisher |
BMC |
series |
Molecular Autism |
issn |
2040-2392 |
publishDate |
2021-01-01 |
description |
Abstract Background PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. Methods Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. Results Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. Limitations Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. Conclusions Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. Trial registration ClinicalTrials.gov Identifier NCT02461446 |
topic |
PTEN Protein Molecular Autism spectrum disorder Cognition Behavior |
url |
https://doi.org/10.1186/s13229-020-00406-6 |
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