| First Author | Leder A | Year | 1999 |
| Journal | Proc Natl Acad Sci U S A | Volume | 96 |
| Issue | 11 | Pages | 6291-5 |
| PubMed ID | 10339580 | Mgi Jnum | J:55195 |
| Mgi Id | MGI:1337475 | Doi | 10.1073/pnas.96.11.6291 |
| Citation | Leder A, et al. (1999) A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice. Proc Natl Acad Sci U S A 96(11):6291-5 |
| abstractText | Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the alpha- or the beta-chain of hemoglobin. The expressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of Lu-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the cu-thalassemia mutation resides [129(Sv/ev)/129(sv/ev) (severe) or 129(SV/eV)/C57BL/6 (mild)], Linkage mapping indicates that the modifying gene is very tightly linked to the beta- globin locus (Lod score = 13.3). Furthermore, the severity of the phenotype correlates with the size of beta-chain- containing inclusion bodies that accumulate in red blood cells and likely accelerate their destruction. The beta- 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 beta-chains. This normal polymorphic variation between murine beta-globin chains could account for the modifying action of the unlinked beta-globin locus. Here, the variation in severity of the phenotype would not depend on a change in the ratio between alpha- and beta-chains but on the chemical nature of the normal beta-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. |
