Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin

The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified...

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Vydané v:Haematologica (Roma) Ročník 96; číslo 5; s. 767 - 770
Hlavní autori: Satta, S., Perseu, L., Moi, P., Asunis, I., Cabriolu, A., Maccioni, L., Demartis, F. R., Manunza, L., Cao, A., Galanello, R.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Pavia Ferrata Storti Foundation 01.05.2011
Predmet:
Adult
Base Sequence
Biological and medical sciences
Brief Reports
DNA Mutational Analysis
Erythrocytes - metabolism
Family Health
Female
Fetal Hemoglobin - metabolism
Fluorometry
HEK293 Cells
Hematologic and hematopoietic diseases
Heterozygote
Humans
Italy
Kruppel-Like Transcription Factors - genetics
Male
Medical sciences
Middle Aged
Mutation
Pedigree
Polymerase Chain Reaction
Protoporphyrins - metabolism
Italy
red cell
Hematology
Red blood cell
Krppel-like factor 1
Fetal hemoglobin
KLF1
Compound heterozygosity
heterozygosity
Blood cell
Protoporphyrin
Fetal cell
Genetics
Mutation
ISSN:0390-6078, 1592-8721, 1592-8721
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Abstract The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1-30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the γ- and β-globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin.
AbstractList The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1-30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the γ- and β-globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin.
The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1–30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (
The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1-30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the γ- and β-globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin.The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1-30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the γ- and β-globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin.
Author Stefania Satta
Isadora Asunis
Franca Rosa Demartis
Paolo Moi
Liliana Maccioni
Laura Manunza
Antonio Cao
Lucia Perseu
Annalisa Cabriolu
Renzo Galanello
AuthorAffiliation 2 Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy
1 Dipartimento di Scienze Biomediche e Biotecnologie-Università di Cagliari, Ospedale Regionale Microcitemie ASL8, Cagliari
AuthorAffiliation_xml – name: 1 Dipartimento di Scienze Biomediche e Biotecnologie-Università di Cagliari, Ospedale Regionale Microcitemie ASL8, Cagliari
– name: 2 Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy
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Issue 5
Keywords red cell
Hematology
Red blood cell
Krppel-like factor 1
Fetal hemoglobin
KLF1
Compound heterozygosity
heterozygosity
Blood cell
Protoporphyrin
Fetal cell
Genetics
Mutation
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Snippet The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic...
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SubjectTerms Adult
Base Sequence
Biological and medical sciences
Brief Reports
DNA Mutational Analysis
Erythrocytes - metabolism
Family Health
Female
Fetal Hemoglobin - metabolism
Fluorometry
HEK293 Cells
Hematologic and hematopoietic diseases
Heterozygote
Humans
Italy
Kruppel-Like Transcription Factors - genetics
Male
Medical sciences
Middle Aged
Mutation
Pedigree
Polymerase Chain Reaction
Protoporphyrins - metabolism
Title Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin
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