期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：11
页码：6291-6295
DOI：10.1073/pnas.96.11.6291
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Thalassemia is a heritable human anemia caused by a variety of mutations that affect expression of the - 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 -thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the -thalassemia mutation resides [129sv/ev/129sv/ev (severe) or 129sv/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 - 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.
