A novel mutation in the human erythroid transcription factor KLF1 as a cause of hereditary persistance of foetal haemoglobin

Abstract

The genetics of the developmental regulation of globin gene expression from gamma to beta globin biosynthesis is not completely understood. Hereditary persistence of foetal hemoglobin (HPFH) which is characterized by persistent post-natal high levels of foetal haemoglobin (HbF > 2.0%) is useful to discover genes involved in the physiology of globin gene control. National Haemoglobin (Hb) testing uncovered a unique type of the Hereditary Persistence of Foetal Haemoglobin (HPFH; GyAy Malta Typp,) among '10 of 29 members from a Maltese family suggesting a dominant allele with variable penetrance due to KlF1 haplo-insufficiency segregating with alleles for the variants Hb I- Malta Ilor a2GY2 117(G19) His~Arg] Hb F Sardinia [or alY2 75 (E19) lIe→ Thr] Hb Valletta [or α2β2 87(F3) Thr~Pro] and possibly other genetic determinants of Hb F. A genome-wide SNP scan followed by linkage analysis was conducted to identify a candidate region on chromosome 19p13.12-13. Sequencing revealed a nonsense mutation in the KlF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KlF1 target genes were downregulated in samples from individuals with HPFH Functional assays suggested that, in addition to its established role in regulating adult globin expression, KlF1 is a key activator of the BCL 11A gene, which encodes a suppressor of Hb F expression. These observations provide a rationale for the effects of KlF1 haploinsufficiency on HbF levels. Although the KlF1 mutation was confirmed as the primary cause of the G γ A γ HPFH Malta Type, the data further suggests that, excluding interplay between the Xmnl and (AT)xTy sites other loci possibly at 11q23.2, 6q22.31 or elsewhere under investigation may account for the variable penetrance of the dominant KlF1 mutation.