A case of congenital dyserythropoietic anemia type IV

Iglesia, Silvia de la; Moreno-Carralero, María-Isabel; Lemes-Castellano, Angelina; Molero-Labarta, Teresa; Méndez, Manuel; Morán-Jiménez, María-Josefa

doi:10.1002/ccr3.825

Cited by 29 publications

(23 citation statements)

References 21 publications

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“…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.…”

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confidence: 99%

“…In general, CDAs are a heterogeneous group of rare hereditary diseases. The CDA type IV is an autosomal dominant inherited blood disorder (27) characterized by ineffective erythropoiesis and by distinct morphological anomalies in the erythroid compartment (blood and bone marrow), such as multinucleated erythroblasts, (39)(40)(41), euchromatin areas connecting the nuclear membrane, atypical cytoplasmic inclusions, and intercellular bridges (27,32). In addition, nonerythroid phenotypes such as growth retardation and disturbance in organ development, particularly urogenital anomalies, are manifested in some of these patients (27,30).…”

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confidence: 99%

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

Kulczyńska

Bieker

Siatecka

2020

Molecular and Cellular Biology

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Krüppel-like factor 1 (KLF1/EKLF) is a transcription factor that globally activates genes involved in erythroid cell development. Various mutations are identified in the human KLF1 gene. The E325K mutation causes congenital dyserythropoietic anemia (CDA) type IV, characterized by severe anemia and non-erythroid-cell-related symptoms. The CDA mutation is in the second zinc finger of KLF1 at a position functionally involved in its interactions with DNA. The molecular parameters of how CDA-KLF1 exerts its biological effects have not been addressed. Here, using an in vitro selection strategy, we determined the preferred DNA-binding site for CDA-KLF1. Binding to the deduced consensus sequence is supported by in vitro gel shifts and by in vivo functional reporter gene studies. Two significant changes compared to wild-type (WT) binding are observed: G is selected as the middle nucleotide, and the 3′ portion of the consensus sequence is more degenerate. As a consequence, CDA-KLF1 did not bind the WT consensus sequence. However, activation of ectopic sites is promoted. Continuous activation of WT target genes occurs if they fortuitously contain the novel CDA site nearby. Our findings provide a molecular understanding of how a single mutation in the KLF1 zinc finger exerts effects on erythroid physiology in CDA type IV.

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confidence: 99%

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confidence: 99%

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

Kulczyńska

Bieker

Siatecka

2020

Molecular and Cellular Biology

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“…In mice, this mutation (E339D) causes neonatal anaemia and hereditary spherocytosis (Siatecka et al, 2010), and so was named 'Nan'. (Arnaud et al, 2010, de-la-Iglesia-Inigo et al, 2017, Jaffray et al, 2013, Ravindranath et al, 2011.…”

Section: Klf1 and Diseasementioning

confidence: 99%

“…Congenital Dyserythropoietic Anaemia is a severe autosomal dominant disease (Arnaud et al, 2010, de-la-Iglesia-Inigo et al, 2017, Jaffray et al, 2013, Ravindranath et al, 2011. As such, patients carry one mutant copy of the gene and one wildtype allele.…”

Section: An Inducible System To Model Congenital Dyserythropoietic Anmentioning

confidence: 99%

“…One such severe anaemia is Congenital Dyserythropoietic Anaemia type IV (CDAIV). CDAIV is a rare autosomal dominant erythrocyte disorder charactered by ineffective erythropoiesis and haemolysis (Arnaud et al, 2010, de-la-Iglesia-Inigo et al, 2017, Jaffray et al, 2013, Ravindranath et al, 2011. CDAIV patients present with severe normocytic anaemia, highly elevated HbF, the presence of nucleated RBCs in the peripheral blood, and erythroid hyperplasia (Mitchell et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Ilsley¹

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Krüppel-like factors (KLFs) are a group of 17 transcription factors with diverse functions such as early embryo patterning, organogenesis and tissue homoeostasis. All 17 members contain highlyconserved DNA-binding domains consisting of three C-terminal C2H2-type zinc fingers. This high level of conservation allows all members of the KLF family to bind to a 9 base pair CACCC-box DNA sequence (CCM CRC CCN) which is commonly found in many tissue-specific gene promoters and enhancers. The activity of each member of the KLF family is largely determined by a more variable N-terminal domain through which they interact with co-factors such as p300 and C-terminal binding protein 2 (CtBP2).Many KLFs are often expressed in the same cells. In these situations, they can form transcriptional networks where they coordinate to control developmental programs. For example, KLF2, KLF4, and KLF5 work redundantly in embryonic stem cells where they regulate key pluripotency genes such as Nanog to maintain the 'stemness' of the cell. Multiple KLFs are expressed during erythropoiesis, the ongoing production of red blood cells, where it is likely that they form transcriptional networks to control differentiation.Krüppel-like factor 1 (KLF1) is an erythroid-specific transcription factor that is responsible for coordinating the expression of a large cohort of genes required for nearly all aspects of erythropoiesis. As the founding member of the KLF group, KLF1 contains three C-terminal C2H2-type zinc fingers that bind to DNA and an N-terminal proline-rich activation domain that interacts with co-factors to initiate transcription of target genes.This thesis investigates the molecular mechanisms of Klf1 binding specificity to DNA and how this is affected by mutations, and by competition between family members.A disease that is known as Congenital Dyserythropoietic anaemia type IV (CDAIV) is a rare autosomal-dominant inherited erythrocyte disorder characterised by ineffective erythropoiesis and haemolysis. CDAIV is caused by a point mutation in the second zinc finger of KLF1 which results in substitution of an amino acid predicted to bind to DNA.A mouse carrying a point mutation in the corresponding amino acid residue in murine Klf1 to that mutated in CDAIV patients has been previously generated in an ENU screen. This mouse displays a semi-dominant haemolytic anaemia and is named 'Nan' for 'neonatal anaemia'. The Nan mouse shares a similar phenotype to that of patients with CDAIV and hereditary spherocytosis.Incredibly, both the 'Nan' and CDAIV mutations cause disease which is far more severe than that of commonly occurring Klf1 haploinsufficiency.ii ChIP-seq analysis in cell lines developed to model Klf1 mutations identified aberrant DNAbinding events genome-wide for both the mouse 'Nan' mutation and the human CDAIV mutation.Next-generation sequencing of newly-synthesised RNA (4sU-RNA-seq) reveals ectopic transcriptional consequences of this aberrant binding. Novel sequence specificity of the mutant protein was confirmed by performi...

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Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature

Deguise

Blain

Simpson

et al. 2023

Pediatric Blood & Cancer

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Congenital dyserythropoietic anemia type IV (CDAIV) is a rare inherited hematological disorder, presenting with severe anemia due to altered erythropoiesis and hemolysis, with variable needs for recurrent transfusions. We present a case of a transfusiondependent male newborn who presented at birth with severe hemolytic anemia, and required an intrauterine transfusion. Genetic testing rapidly identified a Kruppel-like factor 1 (KLF1) pathogenic variant (c.973G>A, p.E325K), known to be causative for CDAIV. This case highlights the advantages of next-generation sequencing testing for congenital hemolytic anemia: diagnostic speed, guidance on natural history, and optimized clinical management and anticipatory guidance for parents and clinicians.Additionally, we reviewed the literature for all CDAIV cases.

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A case of congenital dyserythropoietic anemia type IV

Cited by 29 publications

References 21 publications

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

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

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature

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