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In this study, we report on 8 compound heterozygotes for mutations in the key erythroid transcription factor Krüppel-like factor 1 in patients who presented with severe, transfusion-dependent hemolytic anemia. In most cases, the red cells were hypochromic and microcytic, consistent with abnormalities in hemoglobin synthesis. In addition, in many cases, the red cells resembled those seen in patients with membrane defects or enzymopathies, known as chronic nonspherocytic hemolytic anemia (CNSHA). Analysis of RNA and protein in primary erythroid cells from these individuals provided evidence of abnormal globin synthesis, with persistent expression of fetal hemoglobin and, most remarkably, expression of large quantities of embryonic globins in postnatal life. The red cell membranes were abnormal, most notably expressing reduced amounts of CD44 and, consequently, manifesting the rare In(Lu) blood group. Finally, all tested patients showed abnormally low levels of the red cell enzyme pyruvate kinase, a known cause of CNSHA. These patients define a new type of severe, transfusion-dependent CNSHA caused by mutations in a trans-acting factor (Krüppel-like factor 1) and reveal an important pathway regulating embryonic globin gene expression in adult humans.

Original publication

DOI

10.1182/blood-2013-09-526087

Type

Journal article

Journal

Blood

Publication Date

06/03/2014

Volume

123

Pages

1586 - 1595

Keywords

Adolescent, Adult, Amino Acid Sequence, Anemia, Hemolytic, Child, Child, Preschool, Conserved Sequence, Erythrocyte Indices, Erythrocytes, Female, Fetal Hemoglobin, Gene Expression Regulation, Gene Order, Humans, Infant, Kruppel-Like Transcription Factors, Male, Molecular Sequence Data, Mutation, Protein Binding, Protein Interaction Domains and Motifs, Sequence Alignment, Transfusion Reaction, Young Adult, alpha-Globins, beta-Globins