Mutations in Krüppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

• Published in: Blood Vol. 123; no. 10; pp. 1586 - 1595
• Main Authors: Viprakasit, Vip, Ekwattanakit, Supachai, Riolueang, Suchada, Chalaow, Nipon, Fisher, Chris, Lower, Karen, Kanno, Hitoshi, Tachavanich, Kalaya, Bejrachandra, Sasithorn, Saipin, Jariya, Juntharaniyom, Monthana, Sanpakit, Kleebsabai, Tanphaichitr, Voravarn S., Songdej, Duantida, Babbs, Christian, Gibbons, Richard J., Philipsen, Sjaak, Higgs, Douglas R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.03.2014
• Subjects: Adolescent; Adult; alpha-Globins - metabolism; Amino Acid Sequence; Anemia, Hemolytic - blood; Anemia, Hemolytic - etiology; Anemia, Hemolytic - genetics; beta-Globins - metabolism; Child; Child, Preschool; Conserved Sequence; Erythrocyte Indices; Erythrocytes - metabolism; Female; Fetal Hemoglobin - chemistry; Fetal Hemoglobin - genetics; Gene Expression Regulation; Gene Order; Humans; Infant; Kruppel-Like Transcription Factors - genetics; Male; Molecular Sequence Data; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Sequence Alignment; Transfusion Reaction; Young Adult
• DOI: 10.1182/blood-2013-09-526087
• ISSN: 0006-4971

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. •KLF1 mutations cause severe congenital hemolytic anemia associated with a deficiency of red cell pyruvate kinase.•A severe KLF1 deficiency causes hereditary persistence of embryonic globin synthesis.