dominant negative mutation

**Definition:** A mutant gene product that "poisons" or antagonizes the wild-type product in the same cell. The mutant allele acts in a dominant fashion, and the effect is loss of function, so it differs from a simple loss-of-function allele (haploinsufficiency).

**Pathophysiology:** - The mutant polypeptide is made at normal levels and can still assemble into multimeric complexes (homodimers, trimers, tetramers, polymers, fibrils) with wild-type subunits. - The resulting mixed complexes are nonfunctional. If a protein needs n subunits, the fraction of fully normal complexes in a heterozygote is (1/2)^n. Dimer: 25% of normal. Tetramer: about 6% of normal. - Compare simple haploinsufficiency (e.g., a null allele): about 50% of normal activity remains. - Compare gain-of-function: the mutant protein acquires a new or enhanced activity.

**Key examples (high-yield):** - **Osteogenesis imperfecta (type I collagen, COL1A1/COL1A2):** A glycine substitution in the Gly-X-Y repeat disrupts the triple helix. One abnormal pro-α chain ruins the whole trimer ("procollagen suicide"). Severe forms (e.g., type II, perinatal lethal) are caused by dominant negative missense mutations. Type I (mild) is due to a null allele, i.e., haploinsufficiency (about 50% collagen, a quantitative defect). - **Marfan syndrome (FBN1):** Mutant fibrillin-1 disrupts microfibril assembly. It also causes excess TGF-β signaling. - **Li-Fraumeni syndrome (TP53):** Mutant p53 forms tetramers with wild-type p53 and inactivates them. This is why only one hit is needed in the germline, with loss of heterozygosity (second hit) often following. - **Epidermolysis bullosa simplex (keratin 5/14):** Mutant keratin disrupts intermediate filament networks. - **Familial hypercholesterolemia (LDL receptor, some class mutations):** Some mutations are dominant negative, but most are haploinsufficiency. - **Ehlers-Danlos syndrome (classic and vascular types, e.g., COL3A1):** Defective collagen chains are incorporated into the trimer. - **Dominant negative CFTR, others:** CFTR is autosomal recessive, so it is *not* a typical example. Don't confuse it. - **Others:** Mutant transcription factors that bind DNA but cannot activate transcription (e.g., PPARγ dominant negative mutations causing lipodystrophy and insulin resistance). Dominant negative GPCR/receptor signaling mutants. Mutant Rb or p53 oncoprotein interactions (e.g., viral oncoproteins E6/E7 act functionally similarly but are not mutations).

**Clinical/exam pearls:** - Suspect a dominant negative mechanism when the disease is autosomal dominant and the protein is a structural or multimeric protein (collagen, keratin, fibrillin, p53 tetramer, ion channel tetramers). - Phenotype is often more severe than that from a null allele of the same gene (e.g., OI type II vs type I). - Enzyme deficiencies are usually autosomal recessive because most enzymes are monomeric and 50% activity is sufficient. Structural proteins and multimers tend to be autosomal dominant. - Mechanism comparison: Loss of function (recessive, usually) vs. haploinsufficiency (dominant, 50% activity is insufficient) vs. dominant negative (dominant, <50% activity) vs. gain of function (dominant, new or increased activity).

**Notes:** The "dominant negative" concept was described by Herskowitz (1987) in the context of mutant gene products interfering with wild-type function.