Mutations that impair polypeptide folding commonly result in an unstable and hypofunctional gene product. Their phenotype reflects this loss of function, and the resulting genetic disorder is usually transmitted as a recessive trait. Common forms of cystic fibrosis, hemophilia, and familial hypercholesterolemia are examples of this genetic mechanism in action. A second class of mutations (so-called gain-of-function mutations) encodes proteins with new functions, whose associated disorders are typically transmitted as dominant traits. Some of these are “dominant negative” alleles whose encoded protein can interact with components of the cellular machinery normally accessed by the wild-type gene product. With varying degrees of specificity, these mutations affect the activities of the wild-type allele, for example by disrupting the assembly of a multisubunit complex. Recent observations suggest that gainof-function mutations that affect protein folding can also impair cellular function by less specific mechanisms related to the ability of the mutant protein to challenge the folding capacity in specific cellular compartments. Such mutant proteins are hypothesized to act as proteotoxins and may play a role in important human diseases (1, 2). The paper by Oyadomari et al.(3) appearing in this issue of the JCI addresses important issues related to proteotoxicity in the endoplasmic reticulum (ER).

The Ins2C96Y mutation found in the Akita diabetic mouse precludes formation of an essential disulfide bond between insulin 2 chains and prevents proper folding and processing of this protein. The mutant, malfolded proinsulin-2 is retained in the pancreatic β cell ER (4), presumably by the