Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes

Spinelli, Laura; Black, Fiona; Berg, Jonathan; Eickholt, Britta J.; Leslie, Nicholas R.

doi:10.1136/jmedgenet-2014-102803

Cited by 95 publications

(97 citation statements)

References 31 publications

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“…It found that the majority of these mutations retained most of their phosphatase activity, in contrast to the more severe functional impairment seen in a panel of PTEN mutations that were only reported in cases of PHTS without ASD [50]. These results were recently confirmed by Spinelli et al [51] who reported better AKT inhibition in 7 PTEN mutations seen only in ASD with PHTS cases compared with 5 mutations observed in patients with PHTS with high tumor burdens.…”

Section: Pten Structure Localization and Signalingsupporting

confidence: 77%

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTENassociated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

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Section: Pten Structure Localization and Signalingsupporting

confidence: 77%

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

2015

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“…However, there is also evidence that DISC1 is required for development of glutamatergic synapses [275,276], although it is not yet clear if this function is Wnt-dependent. The gene encoding PTEN, a cytoplasmic protein that suppresses Wnt/β-catenin signaling in the developing mouse cortex [277], has been repeatedly identified as a high-risk ASD susceptibility gene in human genomic studies [278,279,280,281]. Finally, single nucleotide variants of the Wnt/PCP pathway genes PRICKLE1 and PRICKLE2 were identified in whole exome sequencing of affected families [237,282].…”

Section: Human Genomic Studiesmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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“…Therefore, we investigated the effects of the K66R mutation on the expression of unstable PTEN mutant proteins identified in patients with tumor and autism-related syndromes. Additional mutation of K66R increased the protein expression level of the unstable PTEN mutant proteins D252G and H118P, which have been identified in patients with autism (29) and also appeared to have a similar but more modest effect on PTEN L108P, an unstable PTEN mutant protein that has been identified in patients with severe tumor phenotypes (29,30) (Fig. 6, A and B).…”

Section: Resultsmentioning

confidence: 62%

Controlling PTEN (Phosphatase and Tensin Homolog) Stability

Gupta

Leslie

2016

Journal of Biological Chemistry

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Phosphatase and tensin homolog (PTEN) is a phosphoinositide lipid phosphatase and one of the most frequently disrupted tumor suppressors in many forms of cancer, with even small reductions in the expression levels of PTEN promoting cancer development. Although the post-translational ubiquitination of PTEN can control its stability, activity, and localization, a detailed understanding of how PTEN ubiquitination integrates with other cellular regulatory processes and may be dysregulated in cancer has been hampered by a poor understanding of the significance of ubiquitination at individual sites. The function of the phosphatase and tensin homolog (PTEN) 3 tumor suppressor is disrupted in many forms of cancer by diverse mechanisms (1, 2). PTEN is a phosphatidylinositol 3,4,5-trisphosphate lipid phosphatase that acts to oppose the class I phosphoinositide 3-kinases and therefore loss of PTEN function leads to aberrant accumulation of phosphatidylinositol 3,4,5-trisphosphate and activation of downstream oncogenic PI3K-dependent signaling as well as potentially other PI3K-independent changes (2, 3). PTEN is currently known to exist in two forms, a 403-amino acid cytosolic and nuclear protein usually simply called PTEN, and a longer 576-amino acid protein, PTEN-L, which due to its ability to cross cell membranes and inhibit tumor formation when injected into in mice, has been proposed as a protein therapy (4 -6).Although in clinical data from some tumor types, notably breast cancer, reduced PTEN mRNA levels correlate well with reduced PTEN protein (7), in others including prostate cancer, reduced PTEN protein levels are frequently observed in tumors apparently retaining normal levels of PTEN mRNA (8). Among the mechanisms potentially responsible for this selective loss of PTEN protein expression, accelerated degradation by posttranslational ubiquitination seems likely to contribute. This conclusion is supported by the paradigm established for the p53 protein and the ubiquitin E3 ligase MDM2 that destabilization of tumor suppressor proteins can be a significant oncogenic driver and also accumulating evidence for the dysregulation of ubiquitin ligases and proteases that control PTEN stability in several cancer types (9 -12).In addition to its stability, the activity and localization of PTEN can also be controlled by its ubiquitination, notably with PTEN monoubiquitination being linked to its nuclear accumulation (13-15). Several E3 ubiquitin ligases have been proposed to contribute to PTEN ubiquitination, including NEDD4 and the related HECT-domain E3 ligase WWP2, as well as XIAP, CHIP, RFP, SPOP, and MKRN1 (9, 10, 16 -20) and ubiquitin proteases have been identified that can deubiquitinate PTEN, including HAUSP/USP7, OTUD3, and USP13 (11,12,21). Although many of these studies have identified important effects of manipulating these ligases and proteases on PTEN function and often PTEN stability, clear pictures are yet to emerge of the molecular details of these regulatory events, in particular the sites at which PTEN be...

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Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes

Cited by 95 publications

References 31 publications

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Controlling PTEN (Phosphatase and Tensin Homolog) Stability

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