Related Experiment Video
Updated: Jan 7, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
dentification and characterization of novel PAX4 variants in patients with suspected MODY9
Xinyu Chen1,2,3,4,5,6,7, Yang Tian1,3,4,5,6,7, Wanhong Wu1,3,4,5,6,7
1Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Introduction:
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. MODY type 9 (MODY9) is a rare subtype caused by variants in the PAX4 gene. However, the pathogenicity and mechanisms of many PAX4 variants remain unclear. This study aimed to evaluate the clinical relevance and pathogenic mechanisms of three novel PAX4 variants identified in patients with suspected MODY.
Research Design And Methods:
Three unrelated patients with early-onset diabetes and a family history of the disease were screened for PAX4 variants using whole-exome and Sanger sequencing. In silico predictions, evolutionary conservation analysis, and structural modeling were performed. Functional studies were conducted in MIN6 cells to assess protein expression, subcellular localization, and degradation pathways.
Results:
Three novel PAX4 variants (c.83delA; p.Gln28ArgfsTer6, c.35T>C; p.Leu12Pro, and c.488G>C; p.Arg163Pro) were identified. Expression of p.Gln28ArgfsTer6 was undetectable, likely due to nonsense-mediated decay. In contrast, p.Leu12Pro and p.Arg163Pro retained nuclear localization but resulted in markedly reduced protein levels. Treatment with the proteasome inhibitor MG132 restored protein levels of the missense mutants, indicating enhanced proteasomal degradation as the likely mechanism. These findings suggest that certain PAX4 variants impair β-cell function by destabilizing the protein post-translationally.
Conclusions:
This study expands the spectrum of PAX4 variants and provides novel mechanistic insights into the pathogenesis of MODY9. Our results highlight the importance of assessing protein-level consequences for variant interpretation and support the integration of functional assays into MODY genetic diagnostic workflows.
Insights
Three novel PAX4 gene variants were identified in patients with Maturity-onset diabetes of the young (MODY). These PAX4 variants impair beta-cell function by destabilizing the protein, offering new insights into MODY9 pathogenesis.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Maturity-onset diabetes of the young (MODY) is a monogenic diabetes.
- MODY type 9 (MODY9) is caused by variants in the PAX4 gene.
- Pathogenicity of many PAX4 variants remains unclear.
Purpose of the Study:
- Evaluate clinical relevance of three novel PAX4 variants.
- Investigate pathogenic mechanisms of these PAX4 variants.
- Understand MODY9 pathogenesis.
Main Methods:
- Whole-exome and Sanger sequencing identified PAX4 variants.
- In silico predictions and structural modeling were performed.
- Functional studies in MIN6 cells assessed protein expression and degradation.
Main Results:
- Three novel PAX4 variants (p.Gln28ArgfsTer6, p.Leu12Pro, p.Arg163Pro) were identified.
- Missense variants (p.Leu12Pro, p.Arg163Pro) showed reduced protein levels due to enhanced proteasomal degradation.
- Nonsense variant (p.Gln28ArgfsTer6) was undetectable, likely via nonsense-mediated decay.
Conclusions:
- Expands the spectrum of known PAX4 variants.
- Provides mechanistic insights into MODY9 pathogenesis.
- Highlights the importance of assessing protein-level consequences for variant interpretation.
More Related Videos
09:37Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
