Exploring the etiology of haploinsufficiency

Bioessays. 2002 Feb;24(2):175-84. doi: 10.1002/bies.10023.


The focus of this essay is the phenomenon of haploinsufficiency (HI), a manifestation of genetic dominance that arises when only one allele of a normally diploid locus is present. Specifically, I examine the nature of HI for transcription factor genes. Although the concept of HI applies to many such genes, there is a potentially large variety of mechanisms that underlie it. Even when the phenomenon is linked in all cases to reduced absolute gene expression levels, there are several well-documented cases where the explanation is not reduced expression per se but altered stoichiometry. I will discuss the notion of haploimbalance in general and evaluate the property of transcriptional synergy within the context of HI. This kind of non-linear behaviour can probably explain a large proportion of the cases of HI, as well as the variability in most HI phenotypes and the fact that several factors in the same pathway may be dosage sensitive. For the sake of generality, a theoretical analysis of simple non-linear HI systems is also attempted. This article is certainly another preliminary exploration of the complex matters of HI, which remain an intellectual challenge from many points of view.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Dosage
  • Gene Expression Regulation*
  • Genes, Dominant*
  • Humans
  • Macromolecular Substances
  • Models, Genetic
  • Mutation
  • Transcription Factors / genetics*


  • Macromolecular Substances
  • Transcription Factors