Functional Implications of Gene Dosage Effects in Trisomy 21

Summary

Despite the clinical importance of trisomy 21 and other chromosomal abnormalities, very little is known about the mechanisms by which chromosome imbalance results in specific and often highly deleterious phenotypic effects. Gene dosage effects, with direct proportionality be-tween the concentrations of gene products and the number of genes present, have been demonstrated for several loci in both man and mouse. Among these is superoxide dismutase-1 (SOD-1), which is carried by chromosome 21. However, the existence of these primary gene dosage effects does not in itself explain the deleterious outcome of the aneuploid state, and it is therefore necessary to consider the secondary functional consequences of quantitative alterations in the synthesis of gene products. Two general and not necessarily exclusive mechanisms for such secondary effects can be visualized. The first is that aneuploidy interferes indirectly with the delicate regulatory balance among the several chromosomes of a cell and thereby results in a widespread disturbance in the expression of genes on many chromosomes. We have tested this possibility by examining the synthesis of a large number of polypeptides by cultured normal and trisomy 21 fibroblasts and have not been able to detect any generalized disturbance in gene expression.

The second mechanism by which aneuploidy may produce its deleterious effects is by the summation of the specific consequences of the alteration of the dosage of the genes carried by the aneuploid chromosome. These direct secondary effects may be of several types, and to study one possible mechanism we have been investigating the interferon response system in normal and trisomy 21 cells. The locus responsible for the sensitivity of human cells to interferon, IFRC, which is presumed to code for the interferon receptor, is located on chromosome 21. Trisomic cells are three to seven times more sensitive than are normal cells to several of the effects of interferon, including antiviral activity (in fibroblasts), antiproliferative action (in mitogen-stimulated lymphocytes), and inhibition of the maturation of monocytes to macrophages. The enhanced sensitivity of trisomic cells to interferon, considerably greater than the 1.5-fold increase that would be expected on simple gene dosage considerations, may result from the properties of ligand-receptor interactions. However, whatever the cause, this increase in sensitivity illustrates that small changes in gene number can have much greater than proportional effects on the physiologic processes that the gene controls. This may be of considerable significance when attempting to understand the mechanisms by which aneuploidy affects development and function.

Because of the difficulty in working with human cells under controlled conditions, we have been working on the development of an animal model for trisomy 21. As a first step, we have mapped two of the human chromosome 21 loci, SOD-1 and IFRC, on the mouse genome. These loci are syntenic in the mouse and are carried by chromosome 16. Mouse embryos trisomic for chromosome 16 are now being prepared for further study. By studying these aneuploidy embryos and cell lines derived from them, we should gain a better understanding of the functional implications of the genetic imbalance of the genes now known to be on human chromosome 21 and, ultimately, of the mechanisms by which trisomy 21 produces Down’s syndrome in man.