alpha-thalassemia resulting from a negative chromosomal position effect.
To date, all of the chromosomal deletions that cause alpha-thalassemia remove the structural alpha 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 alpha cluster, next to a structurally normal alpha-globin gene, and silences its expression. During development, the CpG island associated with the alpha-globin promoter in the rearranged chromosome becomes densely methylated and insensitive to endonucleases, demonstrating that the normal chromatin structure around the alpha-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.
MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, England.
V M
VM
Barbour
C
C
Tufarelli
J A
JA
Sharpe
Z E
ZE
Smith
H
H
Ayyub
C A
CA
Heinlein
J
J
Sloane-Stanley
K
K
Indrak
W G
WG
Wood
D R
DR
Higgs
D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D019175:DNA Methylation; D005914:Globins / Q000235:genetics; D006801:Humans; D017384:Sequence Deletion; D017085:alpha-Thalassemia / Q000209:etiology / Q000235:genetics*
D005914:Globins