How ER-Retained Mutant Proteins Worsen Genetic Disease: A Double Hit Explained

In this work, we explore how autosomal dominant diseases are shaped by two simultaneous mechanisms: ER retention of misfolded mutant proteins and their ability to interfere with healthy, wild-type versions—a phenomenon known as the dominant-negative effect. Normally, the ER acts as a quality control gate, allowing only properly folded proteins to proceed. However, when mutated proteins get stuck, they can still interact with their functional peers, forming harmful complexes that prevent normal activity.

Our review surveys multiple genetic disorders—including skeletal and connective tissue conditions, vascular and neurological diseases, serpinopathies, and eye disorders—where this combination of ER retention and dominant-negative behavior plays a central role. By consolidating findings across diverse systems, we aim to offer a unifying framework that enhances understanding of genotype-to-phenotype links.