Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.
Synthesis of normal human hemoglobin A, alpha 2 beta 2, is based upon balanced expression of genes in the alpha-globin gene cluster on chromosome 16 and the beta-globin gene cluster on chromosome 11. Full levels of erythroid-specific activation of the beta-globin cluster depend on sequences located at a considerable distance 5' to the beta-globin gene, referred to as the locus-activating or dominant control region. The existence of an analogous element(s) upstream of the alpha-globin cluster has been suggested from observations on naturally occurring deletions and experimental studies. We have identified an individual with alpha-thalassemia in whom structurally normal alpha-globin genes have been inactivated in cis by a discrete de novo 35-kilobase deletion located approximately 30 kilobases 5' from the alpha-globin gene cluster. We conclude that this deletion inactivates expression of the alpha-globin genes by removing one or more of the previously identified upstream regulatory sequences that are critical to expression of the alpha-globin genes.
Liebhaber
S A
SA
Howard Hughes Medical Institute, Department of Human Genetics, University of Pennsylvania, Philadelphia 19104.
Griese
E U
EU
Weiss
I
I
Cash
F E
FE
Ayyub
H
H
Higgs
D R
DR
Horst
J
J
D000328:Adult; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D002885:Chromosomes, Human, Pair 16; D003001:Cloning, Molecular; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005796:Genes; D005838:Genotype; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D005810:Multigene Family; D012313:RNA / Q000097:blood / Q000235:genetics; D015183:Restriction Mapping; D012156:Reticulocytes / Q000378:metabolism
D012313:RNA; D005914:Globins; D004247:DNA