Homeodomain revisited: A lesson from disease-causing mutations

Young In Chi

Research output: Contribution to journalReview articlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)433-444
Number of pages12
JournalHuman Genetics
Issue number6
StatePublished - May 2005
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgments I wish to thank S. Shoelson for initiating the HNF1α project and for insightful discussions. I also thank K. Sarge and members of the Chi laboratory for comments on the manuscript. This work was funded in part by fellowships from the Juvenile Diabetes Research Foundation and the Mary Iacocca Foundation to Y.-I. Chi.


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