Identification of novel genetic modifiers in ß-thalassemia

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The understanding of the phenotypic variability of genetically homogenous disorders represents a major challenge. In b-thalassemia the b-globin gene is affected by a variety of mutations. The group of patients to be analyzed here is homozygous for a splice site mutation that is common in the Middle East. In contrast to this genetic homogeneity the spectrum of the clinical phenotype ranges from mild anemia to most severe, transfusion-depent anemia. We aim at an understanding of this perplexing clinical variability by using a genetic linkage approach to identify modifying factors and by analyzing the effeciency of an mRNA surveillance mechanism that is referred to as nonsense-mediated decay and represents a candidate genetic modifier of b-thalassemia and other genetic disorders.