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An Exploration of the Molecular Pathogenesis of the Autism Component of PTEN Hamartoma Tumor Syndrome (PHTS): Towards an Understanding of PTEN Variation on PHTS Phenotype Diversity

Thacker, Stetson Thomas
http://orcid.org/0000-0001-6050-409X
http://rave.ohiolink.edu/etdc/view?acc_num=case1614788701475458

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Germline alterations of the gene encoding PTEN, a canonical tumor suppressor, contributes to risk of both benign and malignant neoplasia and neurodevelopmental phenotypes, meaning germline PTEN mutations associate with specific rare cancer syndromes (e.g., Cowden syndrome) and autism spectrum disorder (ASD). To describe the PTEN-associated phenotypic heterogeneity, the molecular diagnosis PTEN Hamartoma Tumor Syndrome (PHTS) was established encompassing several clinical entities. The cancer and autism association is a striking, perplexing juxtaposition, inspiring study. Given the mature connection between cancer processes and canonical aspects of PTEN function (i.e. suppression of PI3K/AKT/mTOR signaling), we have focused on PTEN function in neurodevelopmental pathologies like ASD. To investigate this somewhat intractable question (it is challenging to study molecular features of brains in living individuals), we developed two complementary murine models of Pten disruption. The Ptenm3m4 model exhibits cytoplasmic-predominant expression, while the PtenY68H model exhibits nuclear-predominant expression. Prior study of both models found behavioral, cellular, and molecular abnormalities reminiscent of autism. These models are suited for insight into PTEN-ASD pathophysiology and understanding the neurobiological effects of localization-associated, separation-of-function mutants. Herein, we demonstrate that the Ptenm3m4 model shows aberrant alternative splicing with associated changes in splicing factors, U2af2 and Srrm4. Additionally, a multi-omic survey of the Ptenm3m4 brain found dysregulation of molecules and pathways implicated in autism biology, identifying Pten and Psd-95 as regulatory hubs important to initiating and perpetuating observed phenotypes. Intriguingly, these molecular phenotypes undergird numerous changes in neurobiology, including changes in neural stem cell (NSC) maturation, oligodendrocyte (OL) differentiation, and microglia activation. In the PtenY68H model, we found deficits in sociability and increased perseverative behavior, while finding upregulation of genes involved in neuroinflammation, microglia activation, and behavior (e.g., oxytocin). Following the modeling, we sought a comprehensive, clinical perspective on the functional effects of PTEN mutation. Thus, we leveraged variant functionalizing data from deep mutational scanning studies (DMS) compared to PHTS outcomes. We established that variant effects on lipid phosphatase activity and protein stability predict pathogenicity, head circumference, disease burden, and cancer risk (including early onset). This work provides insight on PTEN-ASD pathogenesis and PTEN genotype-phenotype relationships, working toward improved clinical management of PHTS.
Charis Eng, MD, PhD (Advisor)
Zhenghe Wang, PhD (Committee Chair)
Alex Almasan, PhD (Committee Member)
George Stark, PhD (Committee Member)
Rick Padgett, PhD (Committee Member)
Ruth Keri, PhD (Committee Member)
208 p.
Genetics; Neurosciences
PTEN; autism spectrum disorder; cancer; germline; genotype-phenotype

Recommended Citations

Citations

  • Thacker, S. T. (2021). An Exploration of the Molecular Pathogenesis of the Autism Component of PTEN Hamartoma Tumor Syndrome (PHTS): Towards an Understanding of PTEN Variation on PHTS Phenotype Diversity [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1614788701475458

    APA Style (7th edition)

  • Thacker, Stetson. An Exploration of the Molecular Pathogenesis of the Autism Component of PTEN Hamartoma Tumor Syndrome (PHTS): Towards an Understanding of PTEN Variation on PHTS Phenotype Diversity. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1614788701475458.

    MLA Style (8th edition)

  • Thacker, Stetson. "An Exploration of the Molecular Pathogenesis of the Autism Component of PTEN Hamartoma Tumor Syndrome (PHTS): Towards an Understanding of PTEN Variation on PHTS Phenotype Diversity." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1614788701475458

    Chicago Manual of Style (17th edition)

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© 2021, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12