title: A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice.
abstract: 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 alpha-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the alpha-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.
authors.affiliation: Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA 02115, USA. leder@rascal.med.harvard.edu
authors.forename: A
authors.initials: A
authors.lastname: Leder
authors.forename: E
authors.initials: E
authors.lastname: Wiener
authors.forename: M J
authors.initials: MJ
authors.lastname: Lee
authors.forename: S N
authors.initials: SN
authors.lastname: Wickramasinghe
authors.forename: P
authors.initials: P
authors.lastname: Leder
mesh_terms: D000483:Alleles; D000818:Animals; D004912:Erythrocytes / Q000502:physiology / Q000648:ultrastructure; D008040:Genetic Linkage; D005914:Globins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010641:Phenotype; D017085:alpha-Thalassemia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology
chemical_list: D005914:Globins