Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth

Fricano-Kugler, Catherine J.; Getz, Stephanie A.; Williams, Michael R.; Zurawel, Ashley; DeSpenza, Tyrone; Frazel, Paul W.; Li, Meijie; O’Malley, A. James; Moen, Erika L.; Luikart, Bryan W.

doi:10.1016/j.biopsych.2017.11.025

Cited by 28 publications

(28 citation statements)

References 45 publications

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“…Expression of C124S or G129E raised pAKT/AKT levels ( Fig. 5c), consistent with a dominant negative phenotype, as reported previously 15,21,56,57 .…”

Section: Pten Reduction Of Pakt/akt In Hek293 Cells Identifies 25 Novsupporting

confidence: 89%

“…While C124S and G129E have previously been established as dominant negatives, such a characterization of other PTEN variants is sparse 15,21,56,57 . Remarkably, we find 29 variants, including 17 ASD, showing dominant negativity in measures of activated AKT.…”

Section: Discussionmentioning

confidence: 99%

“…By expressing human PTEN variants in Drosophila melanogaster we assess the rate of development in an invertebrate model, regulated by the insulin receptor pathways 17,18 . We test a smaller subset of PTEN variants for effects on neuronal dendritic and axonal growth, and excitatory and inhibitory synaptogenesis using rat primary neuronal cultures, processes found to be disrupted in ASD models 19,20 and mediated by both lipid and protein phosphatase PTEN activities 21,22 . As ASD is primarily defined as disordered behavior and sensorimotor processing, we test impact of variants on chemotaxis in Caenorhabditis elegans.…”

Section: Introductionmentioning

confidence: 99%

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Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

Post

Belmadani

Ganguly

et al. 2019

Preprint

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ABSTRACTFunctional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PHTS, we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occurred across the protein, resulting in partial to complete loss of function (LoF), which was well correlated across models. However, assays were selectively sensitive to variants located in substrate binding and catalytic domains, which exhibited complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.

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“…Expression of C124S or G129E raised pAKT/AKT levels ( Fig. 5c), consistent with a dominant negative phenotype, as reported previously 15,21,56,57 .…”

Section: Pten Reduction Of Pakt/akt In Hek293 Cells Identifies 25 Novsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

Post

Belmadani

Ganguly

et al. 2019

Preprint

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“…While it is possible that these different mechanisms are the direct result of lipid phosphatase activity at the plasma membrane, ASD-associated mutations may specifically disrupt another of PTEN's cellular functions 67,68 . Supporting this idea, some ASD-associated mutations are excluded from the nucleus and lead to neuronal hypertrophy, but this phenotype can be rescued by artificial direction to the nucleus 69 .…”

Section: Discussionmentioning

confidence: 95%

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

Mighell

Evans-Dutson

O’Roak

2018

Preprint

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Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16x10 -5 ) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data. MAIN TEXTRecent large-scale exome sequencing studies have highlighted the abundance of protein-coding variation in the human population 1 . It remains challenging to predict variant pathogenicity and clinical outcomes, especially for genes with pleiotropic effects. With most rare variants private to a single family or individual, using traditional approaches to establish pathogenicity such as variant segregation within a pedigree or identification in independent patients is infeasible. Even for well-studied genes, hundreds of variants are currently defined as variants of uncertain significance (VUS). Moreover, purely computational approaches still suffer from high false positive rates 2 and subjective interpretations that limit the clinical utility of these predictions. To address these challenges for genes of clinical importance, one proposed approach is to prospectively measure the functional effects of all possible mutations, allowing these empirical data to be integrated into the clinical assessment of novel rare variants 3,4 . Historically, these types of functional assays have been conducted in a serial nature, which limits scalability, and often only within a portion of the protein of interest. While there are some notable examples of whole-gene brute force saturation mutagenesis, e.g., TP535 , new more scalable experimental paradigms are being developed that allow the functional dissection of the effects of thousands of genetic mutations in parallel 6 . These approaches leverage recent advances in DNA synthesis and sequencing technologies and have proven particularly valuable in understanding the effects of mutations in cancer-associated genes 7,8 . With these issues in mind, we have developed a saturation mutagenesis approach to...

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“…ASD-related PTEN mutations function mostly in a dominant-negative manner resulting in an unstable but catalytically active gene product, but can also lead to altered subcellular localization. For example, whereas most of the PHTS-linked PTEN mutations are loss-of-function mutations in line with loss of PTEN's canonical tumor-suppressive role, other ASD-associated mutations lead to impaired nucleocytoplasmic shuttling (Rodríguez-Escudero et al 2011;Tilot et al 2014;Spinelli et al 2015;Fricano-Kugler et al 2018;Mingo et al 2018).…”

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confidence: 99%

PTEN in Autism and Neurodevelopmental Disorders

Rademacher

Eickholt

2019

Cold Spring Harb Perspect Med

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Phosphatase and tensin homolog (PTEN) is a classical tumor suppressor that antagonizes phosphatidylinositol 3-phosphate kinase (PI3K)/AKT signaling. Although there is a strong association of PTEN germline mutations with cancer syndromes, they have also been described in a subset of patients with autism spectrum disorders with macrocephaly characterized by impairments in social interactions and communication, repetitive behavior and, occasionally, epilepsy. To investigate PTEN's role during neurodevelopment and its implication for autism, several conditional Pten knockout mouse models have been generated. These models are valuable tools to understand PTEN's spatiotemporal roles during neurodevelopment. In this review, we will highlight the anatomical and phenotypic results from animal studies and link them to cellular and molecular findings.

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Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth

Cited by 28 publications

References 45 publications

Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction

A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

PTEN in Autism and Neurodevelopmental Disorders

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