The molecular basis of HPFH in a British family identified by heteroduplex formation

Abstract

Single-base substitutions in the immediate 5'-flanking region of the fetal G gamma and A gamma globin genes have been associated with non-deletional forms of hereditary persistence of fetal haemoglobin (HPFH). Previously, the sole promoter mutation associated with HPFH in British individuals has been the T to C substitution at position -198 relative to the A gamma globin gene CAP site. We have investigated a British family with G gamma HPFH and found a T to C substitution at position -175 of the G gamma globin gene. The mutation was first detected by examining the amplified 5' regions of both the G gamma and A gamma globin genes for heteroduplex formation after electrophoresis in a Hydrolink gel. The potential of such a system for the study of sequence variations in the gamma gene promoter regions associated with elevated HbF expression has been evaluated. Previously reported cases of an identical mutation in an American-Black and a Sardinian family display haematological phenotypes remarkably similar to that of the British family described here.