Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.

Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family.

Hb Valletta [beta87(F3)Thr-->Pro] and Hb Marseille/Long Island [beta2(NA2)His-->Pro; (-1)Met-(+1)Val-(+2)Pro-Leu], in a unique compound heterozygote with a normal hemoglobin phenotype.

This study refers to the quantitative hemoglobin (Hb) phenotype of a 19-year-old female with Hb Valletta [beta87(F3)Thr-->Pro] in association with Hb Marseille/Long Island [beta2(NA2)His-->Pro; (-1)Met-(+1)Val-(+2)Pro-Leu] and a normal Hb electrophoretogram. The data serve to alert investigators to the possibility that relatives with apparently normal Hb phenotypes may be transmitting mutant alleles and suggest methods for identification.

A review of cis-trans interplay between DNA sequences 5' to the (G)gamma- and beta-globin genes among Hb F-Malta-I heterozygotes/homozygotes and beta-thalassemia homozygotes/compound heterozygotes, and the effects of hydroxyurea on the Hb F/F-erythrocyte; the need for large multicenter trials.

The biosynthesis of Hb F in place of the deficient Hb A could be a suitable treatment for beta hemoglobinopathies. Among newborn Hb F-Malta-I heterozygotes, it could be shown that the XmnI sequence alone had little, if any effect on gamma-globin gene expression, but interplay with the (AT)(X)T(Y) sites in cis and in trans may occur. In contrast, while the XmnI sequence is clearly correlated with gamma-globin levels in anemic adult beta-thalassemia (thal) homozygotes, the effect on F-erythrocyte numbers and Hb F/F-erythrocyte appears independent of the (AT)(X)T(Y) sites.