Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants

Perkins, Andrew C.; Xu, Xiangmin; Higgs, Douglas R.; Patrinos, George P.; Arnaud, Lionel; Bieker, James J.; Philipsen, Sjaak

doi:10.1182/blood-2016-01-694331

Cited by 153 publications

(168 citation statements)

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“…This is clearly different from the cell-intrinsic defects seen with the haploinsufficient or most of the other mutant KLF1 proteins that have been identified in humans (Borg et al, 2011;Helias et al, 2013;Perkins et al, 2016;Singleton et al, 2012;Tallack and Perkins, 2013;Waye and Eng, 2015). What is seen in the present case is a new variant with novel properties that dramatically changes Nan/+ red cell identity.…”

Section: Discussioncontrasting

confidence: 81%

“…However, some mutations lead to anemias (Arnaud et al, 2010;Huang et al, 2015;Jaffray et al, 2013;Singleton et al, 2011;Viprakasit et al, 2014; reviewed by Perkins et al, 2016). The human KLF1 mutation (E325K) in congenital dyserythropoietic anemia (CDA) (Arnaud et al, 2010;Jaffray et al, 2013;Singleton et al, 2011) is at the same amino acid as that seen in the mouse Nan mutant (Heruth et al, 2010;Siatecka et al, 2010b), albeit a different substitution.…”

Section: Introductionmentioning

confidence: 99%

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Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

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Section: Discussioncontrasting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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“…This is especially important as the number of identified KLF1 mutations continue to rise (Magor et al, 2015, Perkins et al, 2016.…”

Section: Discussionmentioning

confidence: 99%

“…A second case has recently been reported (Lee et al, 2016). Given the high frequency of undetected KLF1 mutation carriers (~1:80 in china (Liu et al, 2014a)), it has been suggested that KLF1 mutations may account for a large number of otherwise unexplained cases of severe neonatal anaemia or hydrops foetalis (Magor et al, 2015, Perkins et al, 2016.…”

Section: Klf1 and Diseasementioning

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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Disorders of red cells and platelets

2021

Blood Cells

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Krüppeling erythropoiesis: an unexpected broad spectrum of human red blood cell disorders due to KLF1 variants

Cited by 153 publications

References 64 publications

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

Disorders of red cells and platelets

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