When "loss-of-function" means proteostasis burden: Thinking again about coding DNA variants

Area of Science:

• Genetics and Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• Human genomes contain millions of DNA variants, yet predicting disease outcomes from mutations remains challenging.
• Current models focusing on gene-specific functions inadequately explain variability in inherited diseases.

Purpose of the Study:

• To present a new paradigm for understanding loss-of-function variants based on cellular consequences.
• To enhance clinical prediction and therapeutic precision for genetic disorders.

Main Methods:

• Categorizing missense, nonsense, and frameshift variants by their impact on protein translation and cellular stress responses.
• Integrating concepts of proteostasis, chaperone binding, and cellular adaptation.

Main Results:

• Demonstrated that aberrant protein production affects cellular proteostasis and stress responses.
• Proposed a system to categorize variants for improved clinical prediction.
• Highlighted the potential of all protein-coding variants in contributing to complex diseases.

Conclusions:

• A broader cellular context paradigm improves understanding of variant effects.
• This approach can refine disease prediction and guide precision medicine.
• Further research integrating proteostasis dynamics and aging is crucial for health impacts.