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Mutations in EKLF/KLF1 form the molecular basis of the rare blood group In(Lu) phenotype. 2008

Belinda K Singleton, and Nicholas M Burton, and Carole Green, and R Leo Brady, and David J Anstee
Bristol Institute for Transfusion Sciences (BITS), National Blood Service, United Kingdom. belinda.singleton@nbs.nhs.uk

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.

UI MeSH Term Description Entries
D008188 Lutheran Blood-Group System A complex blood group system having pairs of alternate antigens and amorphic genes, but also subject to a dominant independently segregating repressor. Blood-Group System, Lutheran,Lutheran Blood Group System,System, Lutheran Blood-Group
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009363 Neoplasm Proteins Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm. Proteins, Neoplasm
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004900 Erythroblasts Immature, nucleated ERYTHROCYTES occupying the stage of ERYTHROPOIESIS that follows formation of ERYTHROID PRECURSOR CELLS and precedes formation of RETICULOCYTES. The normal series is called normoblasts. Cells called MEGALOBLASTS are a pathologic series of erythroblasts. Erythrocytes, Nucleated,Normoblasts,Proerythroblasts,Pronormoblasts,Erythroblast,Erythrocyte, Nucleated,Normoblast,Nucleated Erythrocyte,Nucleated Erythrocytes,Proerythroblast,Pronormoblast
D005838 Genotype The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS. Genogroup,Genogroups,Genotypes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man

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