A groundbreaking study published in Nature has revealed that many disease-causing mutations disrupt protein stability, offering new insights into the molecular mechanisms behind genetic disorders. The research, led by scientists from the Center for Genomic Regulation (CRG) in Barcelona and BGI in Shenzhen, analyzed 621 missense mutations—genetic changes that swap one amino acid for another—and found that 61% reduced protein stability.
Unstable proteins are prone to misfolding and degradation, often leading to dysfunction or harmful accumulation in cells. This instability is now linked to heritable cataracts, neurological disorders, developmental conditions, and muscle-wasting diseases.
Key Findings
- Cataracts and Protein Clumping: Researchers found that 72% of cataract-associated mutations in beta-gamma crystallin proteins destabilize them, causing clumping in the eye lens and leading to clouded vision.
- Neurological and Developmental Disorders: Some mutations, like those in the MECP2 gene linked to Rett Syndrome, do not destabilize proteins but disrupt their ability to regulate DNA, impacting brain development.
- Disease Patterns: Recessive disorders are more likely caused by protein instability, while dominant conditions often result from mutations that leave proteins stable but alter their function. For instance, recessive mutations in the CRX protein destabilize it, impairing vision, whereas dominant mutations disrupt its function despite maintaining structural integrity.
A Revolutionary Protein Library
The study leveraged Human Domainome 1, the largest catalog of protein variants ever created, featuring over half a million mutations across 522 protein domains. Using yeast cells engineered to produce mutated proteins, researchers identified mutations that destabilized proteins by observing cell growth—stable proteins allowed yeast to thrive, while unstable ones hindered growth.
Although the catalog covers just 2.5% of human proteins, its findings are already helping researchers predict how mutations affect related proteins. “Data from one protein domain can guide predictions for similar proteins, extending the catalog’s impact,” said ICREA Research Professor Ben Lehner, co-author of the study.
Toward Precision Medicine
This research underscores the importance of understanding whether mutations destabilize proteins or alter their function without affecting stability. “Distinguishing these mechanisms allows for tailored treatments, such as stabilizing unstable proteins or inhibiting harmful activity,” explained Dr. Antoni Beltran, lead author of the study.
As reported by medicalxpress, the researchers aim to expand the catalog to include full-length proteins and map the effects of every possible mutation on human proteins, paving the way for transformative advances in precision medicine.
“This is a critical step toward understanding how mutations drive disease and developing more effective treatments,” concluded Dr. Lehner.