Send to

Choose Destination
J Pathol. 2009 Aug;218(4):409-18. doi: 10.1002/path.2583.

Dominant negative factors in health and disease.

Author information

Institut Jacques Monod, CNRS-UMR 7592, Bâtiment Buffon, 15 Rue Hélène Brion, Paris Cedex 13, France.


The idea of dominant mutations that interfere with the activity of a normal gene product has been known for more than 80 years-the famous Muller's antimorphs. However, only over half a century later, the mechanistic bases of dominant negative mutations (DNMs) were defined in a systematic way by Ira Herskowitz. Most analyses of DNMs consider only intralocus (interallelic) interactions. The typical textbook explanation invokes a defective subunit, which poisons a homo-dimer or a homo-oligomer. More complex cases exist and the quantitative dimension of this phenomenon will be explored here. The basic ideas underlying DN effects can be (and should be) extended to included epistatic (interloci) interactions. Indeed, poisoning heteromeric macromolecular complexes is per se a matter of 'transdominant' negative effects. In this context, non-allelic non-complementation is also considered. Given the importance of DNMs in human disease and in the study of gene function, understanding how they work is essential for understanding pathology and for the design of effective DN molecules that can also prove useful in therapeutics. Finally, the existence and potential relevance of an increasing number of physiological DN protein isoforms is briefly discussed.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center