Review Article

Human Genetics

, Volume 116, Issue 6, pp 433-444

First online:

Homeodomain revisited: a lesson from disease-causing mutations

  • Young-In ChiAffiliated withDepartment of Molecular and Cellular Biochemistry, Center for Structural Biology, University of Kentucky Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access


The homeodomain is a highly conserved DNA-binding motif that is found in numerous transcription factors throughout a large variety of species from yeast to humans. These gene-specific transcription factors play critical roles in development and adult homeostasis, and therefore, any germline mutations associated with these proteins can lead to a number of congenital abnormalities. Although much has been revealed concerning the molecular architecture and the mechanism of homeodomain–DNA interactions, the study of disease-causing mutations can further provide us with instructive information as to the role of particular residues in a conserved mode of action. In this paper, I have compiled the homeodomain missense mutations found in various human diseases and re-examined the functional role of the mutational “hot spot” residues in light of the structures obtained from crystallography. These findings should be useful in understanding the essential components of the homeodomain and in attempts to design agonist or antagonists to modulate their activity and to reverse the effects caused by the mutations.