Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Area of Science:

• Genetics
• Developmental Biology
• Endocrinology

Background:

• Missense variants are common genetic variations.
• The Hedgehog pathway, mediated by GLI2, is crucial for pancreatic beta-cell development in mice.
• The role of GLI2 in human pancreatic development and diabetes is largely unknown.

Purpose of the Study:

• To investigate the functional impact of a heterozygous missense variant in GLI2.
• To determine if this GLI2 variant affects pancreatic beta-like cell differentiation.
• To explore the underlying molecular mechanisms, including pathway crosstalk, in human induced pluripotent stem cells (iPSCs).

Main Methods:

• CRISPR-Cas9 gene editing to create isogenic iPSC lines with the GLI2 variant.
• Differentiation of iPSCs into pancreatic progenitors and endocrine cells.
• RNA sequencing (RNASeq) and network analyses to assess gene expression and pathway activity.

Main Results:

• iPSCs with the GLI2 missense variant exhibited altered GLI2 transcriptional activity.
• Differentiation of pancreatic progenitors into endocrine cells was impaired in variant-carrying iPSCs.
• Analysis revealed dysregulation of non-canonical WNT signaling, indicating crosstalk between Hedgehog and WNT pathways.

Conclusions:

• GLI2 plays an essential role in human endocrine cell development.
• The studied GLI2 missense variant may contribute to early-onset diabetes.
• This research identifies a novel genetic link between GLI2 function and diabetes etiology.