Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant.
The mechanism for elevated production of fetal hemoglobin (Hb F) in a Druze patient with beta zero-thalassemia intermedia was investigated. Heterozygous family members exhibited normal Hb F levels, suggesting that the increase in gamma-gene expression in the propositus may be partly due to anemic stress. Erythroid progenitors of these family members cultured in vitro [burst forming units (erythroid); (BFUe)] showed elevated synthesis of Hb F, indicating the existence of a genetically determined intrinsic capacity for high Hb F production in this family. The propositus was found to be homozygous for a IVS2-position 1 mutation, on the background of Mediterranean haplotype I, which is not known to be linked to high Hb F production. Moreover, extensive molecular studies of the beta-globin gene cluster, including sequence analysis of the promoter regions of the gamma-globin genes, did not reveal any cis- actin mechanism that could account for the high Hb F production in the propositus. A young niece of the propositus with beta zero-thalassemia major was recently discovered, who was homozygous for the same beta-globin allele and haplotype as the propositus. However, unlike her uncle, she does not have a high Hb F level and presents with a severe clinical course. Her inability to produce high Hb F suggests that the genetic determinant for increased gamma-gene expression in the propositus is unlinked to the beta-globin gene cluster.
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.
A
A
Oppenheim
A
A
Yaari
D
D
Rund
E A
EA
Rachmilewitz
D
D
Nathan
C
C
Wong
H H
HH
Kazazian
B
B
Miller
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D005006:Ethnicity; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D013789:Thalassemia / Q000097:blood / Q000235:genetics*
D005914:Globins; D004247:DNA; D005319:Fetal Hemoglobin