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 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

Development of informant‐report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes

“…The pronounced variability and complexity in the profiles of NDD and NPD symptoms, cognitive processing, and adaptive abilities seen in individuals with PHTS (Balci et al, 2018; Busch et al, 2013, 2019; Frazier et al, 2015; Frazier et al, 2021; Hansen‐Kiss et al, 2017; Hobert et al, 2014; Steele et al, 2021; Uljarevic et al, 2021a, 2021b) and other NDGS (Agarwal et al, 2019; Arnett et al, 2018; Berryer et al, 2013; Jimenez‐Gomez et al, 2019; Mulder et al, 2020; Parker et al, 2015; Rai et al, 2018) present a significant assessment challenge. Although a range of currently available and widely‐used instruments have been developed to capture discrete clinical presentations in PHTS and other NGDS, including ASD, ADHD, internalizing and externalizing symptoms, these tools tend to evaluate either a single broad construct or only a subset of relevant symptoms or behaviors.…”

“…Social communication/interaction, daily living skills, executive functioning, and quality of life levels tended to fall 1-2SD below the control mean, and motor skills fell more than 3SD below the control mean. The pronounced variability and complexity in the profiles of NDD and NPD symptoms, cognitive processing, and adaptive abilities seen in individuals with PHTS (Balci et al, 2018;Busch et al, 2013Busch et al, , 2019Frazier et al, 2015;Frazier et al, 2021;Hansen-Kiss et al, 2017;Hobert et al, 2014;Steele et al, 2021;Uljarevic et al, 2021aUljarevic et al, , 2021b and other NDGS (Agarwal et al, 2019;Arnett et al, 2018;Berryer et al, 2013;Jimenez-Gomez et al, 2019;Mulder et al, 2020;Parker et al, 2015;Rai et al, 2018) present a significant assessment challenge. Although a range of currently available and widely-used instruments have been developed to capture discrete clinical presentations T A B L E 2 Factor analysis results by survey scale.…”

Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

“…The Pten gene plays a critical role in the development of dentate granule neurons of the hippocampus, thus determining the synaptic structure and function ( 36 ). Previous work from our laboratory and several others have reported that loss of Pten leads to ASD and alteration in neuronal morphology and physiological function ( 3 , 8 , 54 , 55 ). Conditional Pten KO using different Cre-recombinase delivery methods in mice led to neuronal hypertrophy, seizures, increased dendritic arborization, and increased spine density ( 7 , 8 , 56 , 57 ).…”

Psychiatric Characteristics Across Individuals With PTEN Mutations

“…Importantly, our findings also highlight areas for future investigations, including the mechanisms underlying behavioral problems. In particular, it will be crucial to utilize a multi-level approach to fully characterize the associations between PTEN pathway proteins with individual differences in cognitive, behavioral, and clinical profiles (31). In addition, prospective research should attempt to further understand the impact of both cognitive functioning and ASD traits and explore the role of factors such as emotion regulation, cognitive control and intolerance of uncertainty that have been shown as key risk factors across a range of psychopathologies, in both general clinical (32)(33)(34), ASD (35)(36)(37)(38)(39)(40)(41) and most recently PTEN (42) cohorts.…”