A normal β-globin allele as a modifier gene ameliorating the severity of α-thalassemia in mice

Abstract

Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the ␣-or the ␤-chain of hemoglobin. The expressivity of the phenotype is likely to be inf luenced by unlinked modifying genes. Indeed, by using a mouse model of ␣-thalassemia, we find that its phenotype is strongly inf luenced by the genetic background in which the ␣-thalassemia mutation resides [129 sv͞ev ͞129 sv͞ev (severe) or 129 sv͞ev ͞C57BL͞6 (mild)]. Linkage mapping indicates that the modifying gene is very tightly linked to the ␤-globin locus (Lod score ‫؍‬ 13.3). Furthermore, the severity of the phenotype correlates with the size of ␤-chain-containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The ␤-major globin chains encoded by the two strains differ by three amino acids, one of which is a glycine-to-cysteine substitution at position 13. The Cys-13 should be available for interchain disulfide bridging and consequent aggregation between excess ␤-chains. This normal polymorphic variation between murine ␤-globin chains could account for the modifying action of the unlinked ␤-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between ␣-and ␤-chains but on the chemical nature of the normal ␤-chain, which is in excess. This work also indicates that modifying genes can be normal variants that-absent an apparent physiologic rationale-may be difficult to identify on the basis of structure alone.The severity of thalassemia, one of the most prevalent of the heritable human anemias, is brought about by the insufficient production of functional hemoglobin and the degree of quantitative imbalance between ␣-or ␤-globin chains (1-8). Needless to say, there are a large number of genetic alterations that can cause such a disturbance in globin chain production, and many of these have been characterized at the molecular level (see review in ref. 1). Thus, for example, thalassemias arise through mutations that induce alterations in gene transcription, pre-mRNA splicing, mRNA and protein stability, polyadenylation, and even translation (1). The disease offers a virtual textbook of potential molecular genetic lesions.In addition to the great variety of mutations that affect the expressivity of the phenotype, the phenotype is likely to be further influenced by unlinked modifying genes that could account for the variable severity of the disease seen in certain families wherein the primary genetic lesion is likely to be identical by descent (9-11). To date, save for pathologic hemaglobinopathies, no such modifying genes have been identified.An opportunity to address the issue of modifying genes arose when we created a mouse model of ␣-thalassemia and noted that the severity of the disease was greatly influenced by the genetic background in which the mutation was expressed [129 sv͞ev ͞129 sv͞ev (severe) or 129 sv͞ev ͞C57BL͞6 (mild)] (12). In the work described below, we have identified the modifying gene that ameliorates ...

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