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Expression of mutant mRNA and protein in pancreatic cells derived from MODY3- iPS cells

Shigeharu G Yabe1, Junko Nishida1, Satsuki Fukuda1

  • 1Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Plos One
|May 31, 2019
PubMed

Insights

Maturity-onset diabetes of the young (MODY) research used patient-derived stem cells to study HNF1A gene mutations. Findings suggest MODY3 may result from haplo-insufficiency, not dominant negative effects, due to mutant mRNA decay.

Area of Science:

  • Genetics
  • Endocrinology
  • Stem Cell Biology

Background:

  • Maturity-onset diabetes of the young (MODY) is a monogenic diabetes with over 14 identified genes.
  • Understanding MODY pathogenesis is limited by the inaccessibility of patient pancreatic beta cells.

Purpose of the Study:

  • To investigate the molecular pathology of MODY3 by examining HNF1A gene mutations in patient-derived induced pluripotent stem cells (iPSCs).
  • To differentiate MODY3-iPSCs into pancreatic beta cells and analyze mutant HNF1A mRNA and protein expression.

Main Methods:

  • Established MODY3 patient-derived iPSCs using a non-integrating Sendai virus (SeV) vector.
  • Differentiated iPSCs into pancreatic lineage cells and analyzed HNF1A gene transcripts and proteins.
  • Utilized cycloheximide (CHX) treatment and western blot (WB) analysis.

Main Results:

  • MODY3-iPSCs exhibited pluripotency characteristics.
  • Mutant HNF1A (P291fsinsC) transcripts were less frequent than wild-type but increased with CHX, suggesting nonsense-mediated mRNA decay (NMD).
  • No mutant HNF1A protein bands were detected in differentiated pancreatic cells via WB.

Conclusions:

  • The scarcity of mutant HNF1A protein suggests MODY3 pathogenesis is likely due to haplo-insufficiency rather than a dominant negative effect.
  • Nonsense-mediated mRNA decay (NMD) plays a significant role in degrading mutant HNF1A transcripts in MODY3.
  • Patient-derived iPSCs provide a valuable model for studying MODY pathogenesis.

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