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Complete Loss of PAX4 causes Transient Neonatal Diabetes in Humans
James Russ-Silsby1, Yunkyeong Lee2, Varsha Rajesh2
1Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, U.K.
Medrxiv : the Preprint Server for Health Sciences
|April 16, 2025
Summary
Loss-of-function variants in the PAX4 gene were found in two infants with neonatal diabetes (NDM). These variants caused transient NDM, showing PAX4 is not essential for human beta-cell development.
Area of Science:
- Genetics
- Endocrinology
- Developmental Biology
Background:
- Neonatal diabetes (NDM) offers insights into human pancreatic beta-cell development and function.
- Identifying genetic causes of NDM is crucial for understanding beta-cell biology.
Purpose of the Study:
- To identify genetic variants associated with NDM.
- To investigate the role of PAX4 in human pancreatic beta-cell development and function.
Main Methods:
- Gene discovery in NDM patients.
- CRISPR-edited human induced pluripotent stem cell (iPSC)-derived pancreatic endoderm models.
- CUT&RUN and RNA-sequencing analysis.
- Nonsense-mediated decay confirmation.
Main Results:
- Identified homozygous PAX4 loss-of-function variants (p.(Arg126*) and c.-352_104del) in two unrelated NDM individuals.
- Confirmed p.(Arg126*) variant causes nonsense-mediated decay in iPSC-derived pancreatic endoderm.
- Identified genes regulated by PAX4 involved in islet development and insulin secretion.
- Observed transient NDM in both probands, with relapse, indicating PAX4 is not essential for human beta-cell development.
Conclusions:
- PAX4 loss-of-function variants can cause neonatal diabetes.
- PAX4 plays a role in regulating genes important for pancreatic islet development and glucose-stimulated insulin secretion.
- PAX4 is not essential for the development of human pancreatic beta-cells, unlike findings in mouse models.
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