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

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 PDX1P33T/+, PDX1C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation (PDX1+/-). RESULTS:Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous

SUBMITTER: Wang X 

PROVIDER: S-EPMC6531841 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature