lossoffunction

Loss of function (LOF) refers to a class of genetic alterations that decrease or abolish the activity of a gene product, most often a protein. LOF can affect coding sequences, regulatory regions, or RNA processing, and its phenotypic consequence depends on the organism's genetic context. In diploid species, LOF can be recessive, with a single functional allele sufficient to maintain activity, or dominant if the altered product interferes with the normal one.

Common mechanisms include deletions and frameshift insertions that disrupt open reading frames; nonsense mutations introducing premature stop codons; splice-site mutations that alter mRNA processing; and regulatory changes that markedly reduce transcription. LOF alleles are often contrasted with gain-of-function mutations, which increase activity or confer a new function. LOF alleles can be null (amorphic) with no functional product, or hypomorphic with reduced activity. Some LOF mutations are dominant-negative, where the mutant protein inhibits the normal protein.

In research, LOF mutations are used to infer gene function through knockout approaches in yeast, plants, and animals. Clinically, loss of function of tumor suppressor genes or enzymes can contribute to disease; for example, inactivation of TP53 or BRCA1/2 increases cancer risk. Therapeutically, restoring function or compensating for LOF is a common aim of gene therapy and precision medicine.