PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets

DeSpenza, Tyrone; Carlson, Marina; Panchagnula, Shreyas; Robert, Stephanie M.; Duy, Phan Q.; Mermin-Bunnell, Kellen; Reeves, Benjamin C.; Kundishora, Adam J.; Elsamadicy, Aladine A.; Smith, Hannah; Ocken, Jack; Alper, Seth L.; Jin, Sheng Chih; Hoffman, Ellen J.; Kahle, Kristopher T.

doi:10.1016/j.tins.2021.08.007

Cited by 28 publications

(15 citation statements)

References 137 publications

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“…Lipid-gated Ion channels and several transporters respond differently to PIP 2 and PIP 3 [ 15 ]. The relative concentrations are important as PTEN is an enzyme that converts PIP 3 to PIP 2, and mutation contributes to autism [ 107 ].…”

Section: Future Directionsmentioning

confidence: 99%

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Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

Yuan

Hansen²

2023

Membranes

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Cholesterol and phosphatidyl inositol 4,5-bisphosphate (PIP2) are hydrophobic molecules that regulate protein function in the plasma membrane of all cells. In this review, we discuss how changes in cholesterol concentration cause nanoscopic (<200 nm) movements of membrane proteins to regulate their function. Cholesterol is known to cluster many membrane proteins (often palmitoylated proteins) with long-chain saturated lipids. Although PIP2 is better known for gating ion channels, in this review, we will discuss a second independent function as a regulator of nanoscopic protein movement that opposes cholesterol clustering. The understanding of the movement of proteins between nanoscopic lipid domains emerged largely through the recent advent of super-resolution imaging and the establishment of two-color techniques to label lipids separate from proteins. We discuss the labeling techniques for imaging, their strengths and weakness, and how they are used to reveal novel mechanisms for an ion channel, transporter, and enzyme function. Among the mechanisms, we describe substrate and ligand presentation and their ability to activate enzymes, gate channels, and transporters rapidly and potently. Finally, we define cholesterol-regulated proteins (CRP) and discuss the role of PIP2 in opposing the regulation of cholesterol, as seen through super-resolution imaging.

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Section: Future Directionsmentioning

confidence: 99%

“…Patches can be seen without super-resolution imaging. Adapted from Lang et al, 2001 with permission [ 107 ]. ( B ) Depiction of antibody patching at nanoscopic levels.…”

Section: Figurementioning

confidence: 99%

Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

Yuan

Hansen²

2023

Membranes

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“…Moreover, the functional loss of Pten has also been reported to be linked to ASD. The PTEN gene mutations have been found in about 5% of ASD patients with macroencephaly [ 154 ]. As the role of PTEN in synaptic functioning is associated with ASD, this link can contribute to better understanding of the ASD pathology and promote potential new therapies.…”

Section: Circadian Dysfunction Mtor and Asdmentioning

confidence: 99%

“…A study by Gantois et al showed that hyperactivation of mTORC1 and ERK MAPK pathways is found in Fmr1 knockout mice and metformin ameliorates core behavioral deficits by normalizing ERK hyperactivation [ 160 ]. Targeted Pten deletion in the forebrain leads to aberrant social behaviors in animals [ 140 , 154 ]. Studies found that the Pten mutant mice showing deficits in the social behaviors resembling ASD individuals was associated with the hyperactivity of mTORC1 and its downstream pathway element S6K1.…”

Section: Circadian Dysfunction Mtor and Asdmentioning

confidence: 99%

The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

2022

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Circadian (~24 h) rhythms in physiology and behavior are evolutionarily conserved and found in almost all living organisms. The rhythms are endogenously driven by daily oscillatory activities of so-called “clock genes/proteins”, which are widely distributed throughout the mammalian brain. Mammalian (mechanistic) target of rapamycin (mTOR) signaling is a fundamental intracellular signal transduction cascade that controls important neuronal processes including neurodevelopment, synaptic plasticity, metabolism, and aging. Dysregulation of the mTOR pathway is associated with psychiatric disorders including autism spectrum disorders (ASD) and mood disorders (MD), in which patients often exhibit disrupted daily physiological rhythms and abnormal circadian gene expression in the brain. Recent work has found that the activities of mTOR signaling are temporally controlled by the circadian clock and exhibit robust circadian oscillations in multiple systems. In the meantime, mTOR signaling regulates fundamental properties of the central and peripheral circadian clocks, including period length, entrainment, and synchronization. Whereas the underlying mechanisms remain to be fully elucidated, increasing clinical and preclinical evidence support significant crosstalk between mTOR signaling, the circadian clock, and psychiatric disorders. Here, we review recent progress in understanding the trilateral interactions and propose an “interaction triangle” model between mTOR signaling, the circadian clock, and psychiatric disorders (focusing on ASD and MD).

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“…PTEN, another high confidence autism gene, is a tumor suppressor gene known to function in cell proliferation 82 . To date, >26 variants of CHD8 and >40 variants of PTEN have been identified in autistic probands, and both genes have been estimated to have an 85% penetrance of overgrowth and macrocephaly phenotypes 83,84 . Together, CHD8 and PTEN variants have been estimated to contribute to up to 15% of all ASD-M cases 25 .…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

Nishizaki

Mariano

et al. 2022

Preprint

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Among autistic individuals, a subphenotype with brain enlargement disproportionate to height (autism with disproportionate megalencephaly, or ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we aim to identify additional ASD-DM associated genes to better define the genetic etiology of this subphenotype of autism. Here, we expand the previously studied sample size of ASD-DM individuals ten-fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 153 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include thirteen high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we also narrowed in on additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes previously implicated in ASD or DM alone. Using zebrafish as a model, we performed CRISPR gene editing to generate knockout animals for seven of candidate genes and assessed head-size and induced seizure activity differences. From this analysis, we identified significant morphological changes in zebrafish knockout models of two genes, ythdf2 and ryr3. While zebrafish knockout mutants model haploinsufficiency of assayed genes, we identified a de novo tandem duplication impacting YTHDF2 in an ASD-DM proband. Therefore, we also transiently overexpressed YTHDF2 by injection of in vitro transcribed human mRNA to simulate the patient-identified duplication. Following this, we observed increased head and brain size in the YTHDF2 overexpression zebrafish matching that of the proband, providing a functional link between YTHDF2 mutations and DM. Though discovery of additional mutations of ASD-DM candidate genes are required in order to fully elucidate the genetics associated with this severe form of autism, our study was able to provide support for YTHDF2 as a novel putative ASD-DM gene.

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PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets

Cited by 28 publications

References 137 publications

Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

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