Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults

Gallienne, Alice; Dreau, Hélène; Schuh, Anna; Old, John; Henderson, Shirley

doi:10.3324/haematol.2011.055442

Cited by 72 publications

(66 citation statements)

References 27 publications

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“…Sequencing of genomic DNA and complementary DNA (cDNA) confirmed the insertion was absent from cDNA rendering the patient functionally homozygous for the 2015C>T exon 14 mutation and therefore clinically affected (Fig S3). P38, referred with unclassified CDA, had compound heterozygosity for two pathogenic KLF1 mutations previously reported in CDA‐IV, although not previously documented in the same patient (Gallienne et al , 2012; Viprakasit et al , 2014). The clinical features, early‐onset transfusion‐dependent, microcytic anaemia with reticulocytosis, jaundice, hepatosplenomegaly, high HbF (14·2%) and bone marrow erythroid hyperplasia with binucleate erythroblasts and chromatin bridges, were also consistent with CDA‐IV.…”

Section: Resultsmentioning

confidence: 79%

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

et al. 2016

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SummaryAccurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.

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Section: Resultsmentioning

confidence: 79%

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

et al. 2016

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“…Only moderately elevated HbF (9.5%) was observed in an adult Vietnamese patient who was a compound heterozygote for the c.525_526insCGGCGCC (p.(Gly176Argf-sTer179)) frameshift and c.152T4G (p.(Leu51Arg)) missense mutations in the KLF1 gene. 16 This indicates that an asymptomatic phenotype likely results from a single c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) mutation rather than a combination of two KLF1 mutations, as the c.152T4G (p.(Leu51Arg)) mutation in exon 1 of KLF1 did not alter the activity of the ZF domain. Therefore, KLF1 mutations in the ZF likely give rise to this disease.…”

Section: Discussionmentioning

confidence: 98%

“…14 Studies suggest that the amount and type of mutant KLF1 protein produced are responsible for different RBC phenotypes. [15][16][17][18] Further research is required to determine the relationship between the various KLF1 mutations and the severity of clinical phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

et al. 2015

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Krüppel-like factor 1 (KLF1) regulates erythroid lineage commitment, globin switching, and the terminal maturation of red blood cells. Variants in human KLF1 have been identified as an important causative factor in a wide spectrum of phenotypes. This study investigated two unrelated male children in China who had refractory anemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of hemolysis, along with abnormal hemoglobin (Hb) level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) and one of two missense variants, c.892 G4C (p. (Ala298Pro)) and c.1012C4T (p.(Pro338Ser)). The subjects had microcytic hypochromic anemia, and their healthy parents had single mutation. The two missense mutations affected a highly conserved codon in the zinc finger DNA-binding domain of KLF1, but the protein stability was unaffected in K-562 cells. A KLF1-targeted promoter-reporter assay showed that the two mutations reduce the expression of the HBB, BCL11A, and CD44 genes involved in erythropoiesis, with consequent dyserythropoiesis and an α/non-α chain imbalance. A systematic analysis was performed of the phenotypes associated with the KLF1 mutations in the two families, and the clinical characteristics and differential diagnoses of the disease are presented. This is the first report of an autosomal recessive anemia presenting with microcytic hypochromia, abnormal Hb profile, and other distinctive erythrocyte phenotypes, and provides insight into the multiple roles of KLF1 during erythropoiesis.

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“…In addition, other reports of heterozygous KLF1 mutations in humans either show concomitant disruption of erythropoiesis or show little effect on HbF expression (Arnaud et al 2010;Satta et al 2011). More recent studies suggest that rare variants in KLF1 are indeed associated with elevations in HbF, but this does not appear to occur consistently or to the same extent even with similar mutations (Gallienne et al 2012). The basis of this variation remains to be determined and will be important to better understand the mechanisms by which KLF1 acts both directly and indirectly, to affect HbF expression.…”

Section: The Promise Of Improved Therapies Through Molecular Studies mentioning

confidence: 97%

The Switch from Fetal to Adult Hemoglobin

Sankaran

Orkin

2012

Cold Spring Harbor Perspectives in Medicine

251

178

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The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and b-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and b-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.A s with many facets of the history of the hemoglobin field, the study of the fetal-toadult hemoglobin switch and work on fetal hemoglobin silencing has a rich and storied history that spans the course of several decades. In this work, we begin with a historic overview of this field and then move on to discuss more recent molecular findings that are providing important new insight into this process. There is great hope that these new molecular studies may lead to important targeted therapeutic advances for fetal hemoglobin (HbF) induction. However, the historic work in this field suggests that the road to effective therapies may not always be straightforward and reconsidering seemingly simple observations can often yield important new insights. There are many valuable lessons that can be learned from both the historic and more recent work in this field and therefore we attempt to cover the chronology of findings that have resulted in our current understanding of the fetal-to-adult hemoglobin switch.The disorders of b-hemoglobin, sickle cell disease (SCD) and b-thalassemia, are major sources of morbidity and mortality worldwide (Weatherall et al. 2006). These diseases are the

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Ten novel mutations in the erythroid transcription factor KLF1 gene associated with increased fetal hemoglobin levels in adults

Cited by 72 publications

References 27 publications

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

A novel 33‐Gene targeted resequencing panel provides accurate, clinical‐grade diagnosis and improves patient management for rare inherited anaemias

Compound heterozygosity for KLF1 mutations is associated with microcytic hypochromic anemia and increased fetal hemoglobin

The Switch from Fetal to Adult Hemoglobin

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