A Case of Congenital Dyserythropoeitic Anemia Type IV Caused by E325K Mutation in Erythroid Transcription Factor KLF1

Abstract

Congenital dyserythropoetic anemias (CDA) represent a heterogeneous group of inherited red cell disorders resulting in ineffective erythropoiesis. Several CDA variants have been identified. KLF1 is a transcription factor required for cell division in erythroid differentiation and maturation, and the switch from fetal to adult hemoglobin. Mutations in KLF1 gene can result in a wide range of phenotypes. This case illustrates the E325K mutation in KLF1 presenting with severe anemia in infancy, persistently elevated fetal hemoglobin, and progressive improvement with age. This case of CDA because of KLF1 mutation highlights the common features and expected disease course of CDA type IV.

Clinical and genetic features of congenital dyserythropoietic anemia (CDA)

“…[39][40][41][42][43][44][45][46][47] The same missense variant in the KLF1 gene has been identified in seven CDA type IV patients so far. 18,19,[35][36][37] Therapies for CDA patients depend on the severity of anemia and consist of stem cell transplantation, iron chelation to prevent organ damage, splenectomy to abrogate transfusion requirements or special therapies such as interferonα 48,49 or stem cell transplantation in severe cases of CDA. [50][51][52][53][54][55][56][57][58] Conclusions: New technologies for genetic studies will help to find variants in other genes, in addition to those known, that contribute to or modulate the CDA phenotype or support the correct diagnosis.…”

“…4,24 More than 170 cases of CDA type I, 11,12,25,26 more than 450 cases of CDA type II, 26-34 43 cases of CDA type III, 16 and seven cases of CDA type IV have been published. 18,19,[35][36][37] The Human Gene Mutation Database (http://www.hgmd.cf.ac.…”

“…The actual incidence of these anemias is unknown due to their clinical heterogeneity, the presence of asymptomatic forms and the misdiagnosis of other hereditary hemolytic anemias, although the estimated incidence is 0.5 cases per million inhabitants with a frequency three times higher for CDA type II (0.71 cases/million) than for CDA type I (0.24 cases/million) . More than 170 cases of CDA type I, more than 450 cases of CDA type II, 43 cases of CDA type III, and seven cases of CDA type IV have been published …”

A Krüppel-like factor 1 (KLF1) Mutation Associated with Severe Congenital Dyserythropoietic Anemia Alters Its DNA-Binding Specificity

“…Since we did not have access to CDA type IV patients as this disease is very rare and as only seven cases have been described (26,27,(30)(31)(32)(33)(34)(35)(36)(37)(38), we prepared stable K562 cell lines with doxycycline-inducible expression constructs of WT-KLF1 or CDA-KLF1. We investigated the level of transcription for known KLF1 target genes, which have both types of binding sites for the WT-and CDA-KLF1 variants in their regulatory regions (promoters and/or introns).…”

“…To date, only seven patients suffering from CDA type IV have been described (26,27,(30)(31)(32)(33)(34)(35)(36)(37)(38). In general, CDAs are a heterogeneous group of rare hereditary diseases.…”