Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype.
Comparison of normal erythroblasts and erythroblasts from persons with the rare In(Lu) type of Lu(a-b-) blood group phenotype showed increased transcription levels for 314 genes and reduced levels for 354 genes in In(Lu) cells. Many erythroid-specific genes (including ALAS2, SLC4A1) had reduced transcript levels, suggesting the phenotype resulted from a transcription factor abnormality. A search for mutations in erythroid transcription factors showed mutations in the promoter or coding sequence of EKLF in 21 of 24 persons with the In(Lu) phenotype. In all cases the mutant EKLF allele occurred in the presence of a normal EKLF allele. Nine different loss-of-function mutations were identified. One mutation abolished a GATA1 binding site in the EKLF promoter (-124T>C). Two mutations (Leu127X; Lys292X) resulted in premature termination codons, 2 (Pro190LeufsX47; Arg319GlufsX34) in frameshifts, and 4 in amino acid substitution of conserved residues in zinc finger domain 1 (His299Tyr) or domain 2 (Arg328Leu; Arg328His; Arg331Gly). Persons with the In(Lu) phenotype have no reported pathology, indicating that one functional EKLF allele is sufficient to sustain human erythropoiesis. These data provide the first description of inactivating mutations in human EKLF and the first demonstration of a blood group phenotype resulting from mutations in a transcription factor.
Singleton
Belinda K
BK
Bristol Institute for Transfusion Sciences (BITS), National Blood Service, United Kingdom. belinda.singleton@nbs.nhs.uk
Burton
Nicholas M
NM
Green
Carole
C
Brady
R Leo
RL
Anstee
David J
DJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004900:Erythroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics*; D008188:Lutheran Blood-Group System / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D016335:Zinc Fingers / Q000235:genetics
C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D018076:DNA, Complementary; D051741:Kruppel-Like Transcription Factors; D008188:Lutheran Blood-Group System; D009363:Neoplasm Proteins; C080774:erythroid Kruppel-like factor