Changes in hematological parameters in α‐thalassemia individuals co‐inherited with erythroid Krüppel‐like factor mutations

Yu, Liping; Liu, D.; Cai, Ren; Shang, Xuan; Zhang, X.-H.; Ma, Xiaoxia; Yan, Shanhuo; Fang, Ping; Zheng, Chengguang; Wei, Xiaofeng; Liu, Y.-H.; Zhou, Tianhong; Xu, Xiangmin

doi:10.1111/cge.12443

Cited by 26 publications

(22 citation statements)

References 23 publications

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“…The KLF1 gene has been associated with various phenotypes, both in humans and mice, including hereditary persistence of fetal hemoglobin [19,29,30,31,32,33,34,35]. Recent studies have demonstrated that the KLF1 zinc finger protein regulates the final switch from fetal to adult globin expression using two pathways: directly, it preferentially binds to the promoter element CACCC of the β-gene acting as a switching factor, and indirectly, it binds to a second transcription factor, BCL11A, which in turn plays the role of a repressor of γ-globin expression [31,36,37].…”

Section: Resultsmentioning

confidence: 99%

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

et al. 2016

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Background: The increase in HbA2 is the most important parameter for the identification of thalassemia carriers. However, in routine screening for hemoglobinopathies, some cases are difficult to classify because the level of HbA2 is not typically elevated. In this work, we report the results of a molecular investigation on a cohort of subjects with borderline HbA2. Methods: All subjects with a β-thalassemia carrier partner and a borderline percentage level of HbA2 were investigated for the presence of a pathological mutation in the β-globin gene. All negative subjects were screened for both the KLF1 mutation and the presence of ααα/ or αααα/ alleles. The subjects with reduced MCV and/or MCH were also screened for deletional and nondeletional α-globin gene defects. Results: Various β-globin mutations and KLF1 gene defects are the most common genetic determinants responsible for this phenotype in our population. Conclusion: KLF1 mutations are important in a screening program for hemoglobinopathies. An increase in HbF in association with borderline HbA2 levels is a useful but not exclusive marker that suggests the investigation of this gene. On the basis of our findings, we are able to suggest the molecular procedure to use in a population characterized by a high prevalence of thalassemia carriers.

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Section: Resultsmentioning

confidence: 99%

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

et al. 2016

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“…55 There is a mild but statistically significant decrease in mean cell volume in the presence of a class 2 or 3 KLF1 variant, but this is not noticeable in routine diagnostics ( Figure 3). 55 KLF1 directly activates the HBB gene, 11,12,45 and partial correction of the a-globin:b-globin chain ratios would be expected to ameliorate disease severity.…”

Section: Prevalence Of Klf1 Variants and Interactions With Hemoglobinmentioning

confidence: 95%

“…In Southern China, the combined incidence of class 2 and 3 KLF1 variants (1.3%) is remarkably high, whereas in Northern China it is low, which correlates with the distribution of hemoglobinopathies in these regions. Consequently, co-inheritance of hemoglobinopathies and KLF1 variants is common 7,55 and is likely to be the case in other areas where hemoglobinopathies are endemic such as the Mediterranean 8,47 and Southeast Asia. 4,[55][56][57] The incidence of KLF1 mutations in Africa has not been tested, although there are reports of KLF1 variants in patients of African descent.…”

Section: Prevalence Of Klf1 Variants and Interactions With Hemoglobinmentioning

confidence: 99%

“…Consequently, co-inheritance of hemoglobinopathies and KLF1 variants is common 7,55 and is likely to be the case in other areas where hemoglobinopathies are endemic such as the Mediterranean 8,47 and Southeast Asia. 4,[55][56][57] The incidence of KLF1 mutations in Africa has not been tested, although there are reports of KLF1 variants in patients of African descent. 58 Sequence analysis of KLF1 in 32 samples representing the lower and upper 10th percentiles of the HbF values from 250 patients with sickle cell diseases indicates that KLF1 variants are not commonly associated with increased HbF in populations of African descent (Swee-Lay Thein, unpublished data).…”

Section: Prevalence Of Klf1 Variants and Interactions With Hemoglobinmentioning

confidence: 99%

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

Perkins

Higgs

et al. 2016

Blood

153

157

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Until recently our approach to analyzing human genetic diseases has been to accurately phenotype patients and sequence the genes known to be associated with those phenotypes; for example, in thalassemia, the globin loci are analyzed. Sequencing has become increasingly accessible, and thus a larger panel of genes can be analyzed and whole exome and/or whole genome sequencing can be used when no variants are found in the candidate genes. By using such approaches in patients with unexplained anemias, we have discovered that a broad range of hitherto unrelated human red cell disorders are caused by variants in KLF1, a master regulator of erythropoiesis, which were previously considered to be extremely rare causes of human genetic disease.

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“…Only with the combination of two defective alleles do the patients exhibit symptoms, allowing the mutations to be passed with no harm to the carrier. In fact, there are suggestions that some mutations in KLF1 can ameliorate the symptoms of diseases such as haemoglobinopathies as they are more common in thalassemia endemic regions (Liu et al, 2014a, Yu et al, 2014 and can result in high expression of foetal haemoglobins.…”

Section: Klf1 and Diseasementioning

confidence: 99%

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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Changes in hematological parameters in α‐thalassemia individuals co‐inherited with erythroid Krüppel‐like factor mutations

Cited by 26 publications

References 23 publications

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

The Problem of Borderline Hemoglobin A2 Levels in the Screening for β-Thalassemia Carriers in Sardinia

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

Investigating the Molecular Pathogenesis of Inherited Childhood Anaemia

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