alpha-thalassemia resulting from a negative chromosomal position effect

To date, all of the chromosomal deletions that cause alpha-thalassemia remo ve the structural alpha genes and/or their regulatory element (HS -40), A u nique deletion occurs in a single family that juxtaposes a region that norm ally lies approximately 18-kilobase downstream of the human alpha cluster, next to a structurally normal alpha-globin gene, and silences its expressio n. During development, the CpG island associated with the alpha-globin prom oter in the rearranged chromosome becomes densely methylated and insensitiv e to endonucleases, demonstrating that the normal chromatin structure aroun d the alpha-globin gene is perturbed by this mutation and that the gene is inactivated by a negative chromosomal position effect. These findings highl ight the importance of the chromosomal environment in regulating globin gen e expression. (C) 2000 by The American Society of Hematology.