• About
    • Login
    View Item 
    •   Institutional Repository Home
    • School of Medicine
    • Cell & Developmental Biology
    • View Item
    •   Institutional Repository Home
    • School of Medicine
    • Cell & Developmental Biology
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of Institutional RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsDepartmentThis CollectionBy Issue DateAuthorsTitlesSubjectsDepartment

    My Account

    LoginRegister

    Point mutations in the PDX1 transactivation domain impair human beta-cell development and function

    Wright, Christopher V. E.
    : http://hdl.handle.net/1803/10033
    : 2019-06

    Abstract

    Objective: Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown. Methods: In this study, we screened a large cohort of subjects with increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1(P33T/)(+), PDX1(C18R/+) mutations and engineered isogenic cell lines carrying homozygous PDX1(P33T/P33T), PDX1(C18R/C18R) mutations and a heterozygous PDX1 loss-of-function mutation (PDX1(+/-)). Results: Using an in vitro beta-cell differentiation protocol, we demonstrated that both, heterozygous PDXP33T/+, PDX1(C18R/+)and homozygous PDX1(P33T/P33T), PDX1(C18R/C18R) mutations impair beta-cell differentiation and function. Furthermore, PDX1(+/-) and PDX1(P33T/P33T )mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1 -bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1(P33T/+ )and PDX1(P33T/P33T) mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion. Conclusions: Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and beta-cell function and contribute to the predisposition for diabetes. (C) 2019 The Authors. Published by Elsevier GmbH.
    Show full item record

    Files in this item

    Thumbnail
    Name:
    Point mutations in the PDX1 ...
    Size:
    6.498Mb
    Format:
    PDF
    View/Open

    This item appears in the following collection(s):

    • Cell & Developmental Biology

    Connect with Vanderbilt Libraries

    Your Vanderbilt

    • Alumni
    • Current Students
    • Faculty & Staff
    • International Students
    • Media
    • Parents & Family
    • Prospective Students
    • Researchers
    • Sports Fans
    • Visitors & Neighbors

    Support the Jean and Alexander Heard Libraries

    Support the Library...Give Now

    Gifts to the Libraries support the learning and research needs of the entire Vanderbilt community. Learn more about giving to the Libraries.

    Become a Friend of the Libraries

    Quick Links

    • Hours
    • About
    • Employment
    • Staff Directory
    • Accessibility Services
    • Contact
    • Vanderbilt Home
    • Privacy Policy