α-Thalassemia resulting from a negative chromosornal position effect

To date, all of the chromosomal deletions that cause α-thalassemia remove the structural α genes and/or their regulatory element (HS -40). A unique deletion occurs in a single family that juxtaposes a region that normally lies approximately 18-kilobase downstream of the human α cluster, next to a structurally normal α-globin gene, and silences its expression. During development, the CpG island associated with the α-globin promoter in the rearranged chromosome becomes densely methylated and insensitive to endonucleases, demonstrating that the normal chromatin structure around the α-globin gene is perturbed by this mutation and that the gene is inactivated by a negative chromosomal position effect. These findings highlight the importance of the chromosomal environment in regulating globin gene expression. (C) 2000 by The American Society of Hematology.