loss of function mutation
Summary
A loss-of-function (LOF) mutation reduces or eliminates the normal activity of a gene product, often resulting in a null (amorphic) or hypomorphic allele. These mutations are typically recessive in inheritance (one normal allele can compensate), though haploinsufficiency can cause dominant phenotypes if 50% protein levels are insufficient for normal function.
Detail
LOF mutations decrease or abolish protein function through mechanisms such as nonsense mutations (premature stop codons), frameshift mutations, deletions, splice site mutations, or missense mutations that disrupt critical structural/functional domains. The resulting protein may be nonfunctional, unstable, or absent entirely (null allele) or retain partial function (hypomorphic allele).
Inheritance pattern: Most LOF mutations are recessive because one functional copy of a gene typically produces enough protein for normal physiology (e.g., enzyme deficiencies in metabolic disorders like phenylketonuria, CFTR mutations in cystic fibrosis). However, some genes are haploinsufficient—dosage-sensitive genes where 50% protein levels are inadequate—leading to dominant inheritance (e.g., LDL receptor mutations in familial hypercholesterolemia, PTEN in Cowden syndrome, tumor suppressor genes like TP53, RB1 in Knudson's two-hit hypothesis).
Dominant-negative effect is a special case where a mutant protein not only loses its own function but also interferes with the wild-type protein product, often in multimeric proteins (e.g., collagen mutations in osteogenesis imperfecta, p53 mutations in Li-Fraumeni syndrome).
Clinical relevance: LOF mutations underlie many single-gene disorders and are contrasted with gain-of-function (GOF) mutations, which confer new or enhanced protein activity (e.g., RAS oncogenes, achondroplasia FGFR3 mutations). Understanding LOF vs. GOF is essential for predicting inheritance patterns, designing genetic counseling strategies, and developing targeted therapies (e.g., enzyme replacement for LOF enzyme deficiencies vs. small molecule inhibitors for GOF oncogenic mutations).
Examples for boards: CFTR (cystic fibrosis, LOF, recessive), LDLR (familial hypercholesterolemia, LOF, dominant via haploinsufficiency), tumor suppressor genes (RB1, TP53, APC—LOF requires "two-hit" inactivation), Factor V Leiden (GOF, for contrast), RET proto-oncogene (GOF in MEN2, LOF in Hirschsprung disease—same gene, different mutation types causing distinct diseases).
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- Thompson & Thompson Genetics in Medicine
- Molecular Biology of the Cell (Alberts et al.)
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.