Open reading frame point mutations are associated with a variety of diseases, including Alzheimer’s, and many of these mutations destroy the function of the protein in question. But what of the expression level of the mutated gene? This question was addressed by Kenneth Kinzler and colleagues in 16 August Science.

First author Hai Yan and coworkers, Johns Hopkins Medical Institutions, Baltimore, Maryland, looked at single nucleotide polymorphisms (SNPs) in thirteen genes from 96 families in the Centre d'Etude du Polymorphisme Humain (CEPH) database. They found altered levels of gene expression in 6 of the thirteen genes, affecting as many as 30 percent of individuals in the case of the protein p73. Expression levels ranged from 1.3- to 4.3-fold of those seen with wild-type alleles. Furthermore, the authors were able to follow Mendelian patterns of inheritance in three families, two with a SNP in the gene for calpain-10, and one with a mutation in protein kinase D2. Those with an inherited mutation consistently had 1.5-fold (PKD2) or 0.5-fold (Calpain-10) normal levels of expression.

What does this mean for those studying polymorphisms and disease? For one thing it suggests that inherited variations in expression may underlie disease phenotypes. In Alzheimer’s disease, for example, it has been clearly shown that levels of the e4 variant of the apolipoprotein E gene, a known risk factor for AD, are much lower than those of the wild type in both plasma and brain (see, for example, Beffert et al., 1997). But it remains to be seen whether these differences are due to changes in expression or changes in structure, which, in turn, may affect turnover, sequestration, stability, etc. In any case, “it’s the protein that counts, and biological activity stems from protein alterations, not whether mRNA is going up or down or is spliced differently” says Judes Poirier, McGill University, Montréal. “It does not mean that it is not important. It is just that mRNA humor does not necessarily bear on physiology.”—Tom Fagan


  1. It is interesting [that] the authors show that some fraction of genes with allelic variation have differential expression of the alleles present. This theoretically could affect certain disease pathways depending on the genes involved. To my knowledge, there is not good evidence that this type of change occurs secondary to differential expression of apoE alleles. Plus, given the differences between the function of apoE isoforms in regard to properties such as Ab levels and deposition, I suspect that the effects described in this paper are not likely at play with apoE and Alzheimer's. It probably should be examined, however, at the level of the apoE mRNA and protein within the CNS in a rigorous fashion. The paper makes a good point, though, that for any gene related to a disease that has different allelic variants, this effect should probably be looked for as an alternative reason for why a particular allele may be disease-linked.

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External Citations

  1. Beffert et al., 1997

Further Reading

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Primary Papers

  1. . Allelic variation in human gene expression. Science. 2002 Aug 16;297(5584):1143. PubMed.