Blood group phenotypes resulting from mutations in erythroid transcription factors

This review describes the genetics of unusual blood group phenotypes, particularly those with altered expression of Lutheran antigens, and how this area of study has informed our understanding of erythropoiesis in general and haemoglobin switching in particular.

Mutations in erythroid transcription factors GATA1 (GATA1 binding protein 1) and KLF1 (Kruppel-like factor 1) cause benign and disease phenotypes in humans [X-linked Lu(a-b-) phenotype, In(Lu) blood group phenotype, hereditary persistence of foetal haemoglobin, borderline HbA(2), and congenital dyserythropoietic anaemia (CDA)]. These studies explain the occurrence of rare blood group phenotypes with simultaneous altered expression of antigens from several blood group systems and illuminate the role of KLF1 in gamma and delta globin gene regulation.

The study of rare blood group phenotypes is a potent tool for discovery of mutations in human genes. Elucidation of the molecular basis of the rare In(Lu) phenotype revealed the first mutations in human KLF1. Subsequently, numerous additional mutations have been described, one of which causes a rare form of CDA. Analysis of the X-linked Lu(a-b-) phenotype revealed a mutation in the C-terminal domain of human GATA1. The apparent sensitivity of the Lutheran glycoprotein to alterations in GATA1 and KLF1 activity suggest that it could be a useful biomarker of erythroid transcription factor mutation.