Alterations on high HbF levels may be associated with KLF1 gene mutations

M. Aydin; E. Rencuzogullari; S. Bayram; Y. Sevgiler; A. Genc

doi:10.14715/KLF1; Fetal hemoglobin; Globin genes; Variations.

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Vol. 63 No. 8: Issue 8

Issue Published : September 4, 2017

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Alterations on high HbF levels may be associated with KLF1 gene mutations

https://doi.org/10.14715/KLF1;%20Fetal%20hemoglobin;%20Globin%20genes;%20Variations.

M. Aydin

Departmant of Biology, Faculty of Science and Letters, Adiyaman University, Adiyaman, Turkey

E. Rencuzogullari

Departmant of Biology, Faculty of Science and Letters, Adiyaman University, Adiyaman, Turkey

S. Bayram

Department of Nursing, School of Health, Adiyaman University, Adiyaman, Turkey

Y. Sevgiler

Departmant of Biology, Faculty of Science and Letters, Adiyaman University, Adiyaman, Turkey

A. Genc

Vocational School of Health Services, Adiyaman Univesity, Adiyaman, Turkey

Corresponding Author(s) : E. Rencuzogullari

erencuzogullari@adiyaman.edu.tr

Cellular and Molecular Biology, Vol. 63 No. 8: Issue 8
Article Published : August 30, 2017

Abstract

The KLF1 gene synthesizes a transcription factor in the zinc finger structure that regulates the transcription of Î²-, Î³-globin, and Foxm1 genes. This factor plays an important role in the erythropoiesis mechanism by modifying the chromatin structure and is involved in the regulation of transcription in the opening of the Î²-globin gene. Î²-globin gene expression could be disrupted by a mutation, which may be a possible cause of a disruption in regulation of the promotor of the Î²-globin gene where the KLF1 transcription factor binds. This can lead to an inherited high fetal hemoglobin (HbF) ratio in people. Therefore, the main aim of this study was to determine the effects of KLF1 mutations on these high levels of HbF. In this study, in order to determine the relationship between the KLF1 mutations and the high HbF levels three exons along with the 5'-UTR and 3'-UTR regions of the KLF1 gene were sequenced of 53 volunteers. In this study, 3 variations in the non-coding regions of the KLF1 gene were not associated with a high level of HbF. Five variations were detected in the second exon of KLF1 gene. One of these is a frame shift that occurs when GG bases are inserted between the 59-60 codons, and the other four variations occur as a base substitution variations. No correlation was found between high HbF levels and neutral variants. Only polar-nonpolar amino acid changes were found at two points. At one of them, a significant drop in the high HbF levels was observed, while the other was observed to be high near to the critical limit. These findings suggested that variations in function of the KLF1 gene can alter the HbF levels.

Keywords

KLF1 fetal hemoglobin globin genes variations

Aydin, M., Rencuzogullari, E., Bayram, S., Sevgiler, Y., & Genc, A. (2017). Alterations on high HbF levels may be associated with KLF1 gene mutations. Cellular and Molecular Biology, 63(8), 51–57. https://doi.org/10.14715/KLF1; Fetal hemoglobin; Globin genes; Variations.

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References

Bouva MJ, Harteveld CL, Bakker-Verweij G, van Delft P, Giordano PC. GÎ³ -37 (A-T): A new nondeletional hereditary persistence of fetal hemoglobin determinant associated with the rare codon 91 (+t) d0-thalassemia. Hemoglobin 2006; 30:371–7.
De Andrade TG, Peterson KR, Cunha AF, Moreira LS, Fattori A, Saad STO, Costa FF. Identification of novel candidate genes for globin regulation in erythroid cells containing large deletions of the human Î²-globin gene cluster. Blood Cells Mol Dis 2006; 37:82–90.
Forget BG. Molecular Basis of Hereditary Persistence of Fetal Hemoglobin. Cooly's Anemia: Seventh Symp. 2006; 850:438-46.
Gallagher PG. HbA2: at the borderline of the KLF. Blood 2011; 118:4301-2.
Genç A. Hemoglobin Varyantlarının DNA Dizi Analizi ile Belirlenmesi. í‡ukurova íœniversitesi, Sağlık Bilimleri Enstitüsü, 2005; Master's Thesis, Adana/TURKEY.
Gonzales-Redondo JM, Kutlar F, Kutlar A, Stroming TA, Pablos JM, Kılınç Y, Huisman THJ. HbS (C) Î²--thalassemia: different mutations are associated with different leves of normal HbA. Brit J Haematol 1998; 70:85-9.
Grieco AJ, Billett HH, Green NS, Driscoll MC, Bouhassira EE. Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1. PLoS One 2015; 10(6):e0129431.
Huisman THJ, Carver MFH, Efremov GD. Syllabus of Human Hemoglobin Variants. Augusta: The Sickle Cell Anemia Foundation; 1996.
Lee ST, Yoo EH, Kim JY, Kim JW, Ki CS. Multiplex ligation-dependent probe amplification screening of isolated increased HbF levels revealed three cases of novel rearrangements/deletions in the ï¢-globin gene cluster. Bri J Haematol 2009; 148:154-60.
Lukens JN. The abnormal hemoglobins: General principles. In: Lee G R, Foerster J, Lukens J, Poraskev F, Greer J, Rodgers G M. Eds. Wintrobe's Clinical Hematology, 10th ed., Eygp: Mass Publishing Co., 1999, pp. 1329-1343.
Magor GW, Tallack MR, Gillinder KR, Bell CC, McCallum N, Williams B, Perkins AC. KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. 2015; 125:2405-17.
Manca L, Masala B. Disorders of the Synthesis of Human Fetal Hemoglobin, IUBMB Life 2008; 60:94-111.
Nagel RL. Disorder of Hemoglobin Function and Stability. Handin R I, Lux S E and Stossel T P. Blood: Principles and Practice of Hematology. Philadelpphia: Lippincott Williams&Wilkins, 2003, pp. 1597-1654.
Pereira C, Relvas L, Bento C, Abade A, Ribeiro ML, Manco L. Polymorphic variations influencing fetal hemoglobin levels: Association study in beta-thalassemia carriers and in normal individuals of Portuguese origin. Blood Cells Mol Dis 2015; 54:315–20.
Radmilovic M, Zukic B, Petrovic MS, Bartsakoulia M, Stankovic B, Kotur N, Dokmanovic L, Georgitsi M, Patrinos GP, Pavlovic S. Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. Ann Hematol 2013; 92:53-8.
Rochette J, Craig JE, Thein SL. Fetal Hemoglobin Levels in Adults. Blood Rev 1994; 8:213-24.
Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudine M, Bender MA, Tucker PW, Orkin SH. Developmental and species-divergent globin switching are driven by BCL11A. Nature 2009; 460:1093-7.
Shariati L, Khanahmad H, Salehi M, Hejazi Z, Rahimmanesh I, Tabatabaiefar MA, Modarressi MH. Genetic disruption of the KLF1 gene to overexpress the Î³-globin gene using the CRISPR/Cas9 system. J Gene Med 2016; 18:294-301.
Stoming TA, Stoming GS, Lanclos KD, Fei YJ, Altay C, Kutlar F, Huisman THJ. An AÎ³ type of nondeletional hereditary persistence of fetal hemoglobin with a Tâ†’C mutation at position –175 to the cap site of the AÎ³ globin gene. Blood 1989; 73:329-33.
Åžişli N. Vücut Proteinleri ve Fonksiyonları. Onat T, Emerk K, Sözmen e Y. ć°nsan biyokimyası. Ankara: Palme yayıncılık, 2002, pp. 135-44.
Tasiopoulou M, Boussiou M, Sinopoulou K, Moraitis G, Loutradi-Anagnostou A, Karababa P. G gamma-196 C-->T, A gamma-201 C-->T: two novel mutations in the promoter region of the gamma-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece. Blood Cells Mol Dis 2008; 40:320-2.
Thompson M, Mcinnes RR, Willard HF. Genetics in Medicine. 5th ed., Philadelphia: B. Saunders Comp., 1991, pp. 247-70.
Vinjamur DS, Wade KJ, Mohamad SF, Haar JL, Sawyer ST, Lloyd JA. Krüppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation. Haematologica 2014; 99:1565-73.
Wang T, He Y, Zhou JY, Xie XM, Li J, Li R, Liao C, Li DZ. KLF1 gene mutations in Chinese adults with increased fetal hemoglobin. Hemoglobin 2013; 37:501-6.
Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th. Ed., Blackwell science, 2001, pp. 64-120.

References

Bouva MJ, Harteveld CL, Bakker-Verweij G, van Delft P, Giordano PC. GÎ³ -37 (A-T): A new nondeletional hereditary persistence of fetal hemoglobin determinant associated with the rare codon 91 (+t) d0-thalassemia. Hemoglobin 2006; 30:371–7.

De Andrade TG, Peterson KR, Cunha AF, Moreira LS, Fattori A, Saad STO, Costa FF. Identification of novel candidate genes for globin regulation in erythroid cells containing large deletions of the human Î²-globin gene cluster. Blood Cells Mol Dis 2006; 37:82–90.

Forget BG. Molecular Basis of Hereditary Persistence of Fetal Hemoglobin. Cooly's Anemia: Seventh Symp. 2006; 850:438-46.

Gallagher PG. HbA2: at the borderline of the KLF. Blood 2011; 118:4301-2.

Genç A. Hemoglobin Varyantlarının DNA Dizi Analizi ile Belirlenmesi. í‡ukurova íœniversitesi, Sağlık Bilimleri Enstitüsü, 2005; Master's Thesis, Adana/TURKEY.

Gonzales-Redondo JM, Kutlar F, Kutlar A, Stroming TA, Pablos JM, Kılınç Y, Huisman THJ. HbS (C) Î²--thalassemia: different mutations are associated with different leves of normal HbA. Brit J Haematol 1998; 70:85-9.

Grieco AJ, Billett HH, Green NS, Driscoll MC, Bouhassira EE. Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1. PLoS One 2015; 10(6):e0129431.

Huisman THJ, Carver MFH, Efremov GD. Syllabus of Human Hemoglobin Variants. Augusta: The Sickle Cell Anemia Foundation; 1996.

Lee ST, Yoo EH, Kim JY, Kim JW, Ki CS. Multiplex ligation-dependent probe amplification screening of isolated increased HbF levels revealed three cases of novel rearrangements/deletions in the ï¢-globin gene cluster. Bri J Haematol 2009; 148:154-60.

Lukens JN. The abnormal hemoglobins: General principles. In: Lee G R, Foerster J, Lukens J, Poraskev F, Greer J, Rodgers G M. Eds. Wintrobe's Clinical Hematology, 10th ed., Eygp: Mass Publishing Co., 1999, pp. 1329-1343.

Magor GW, Tallack MR, Gillinder KR, Bell CC, McCallum N, Williams B, Perkins AC. KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome. 2015; 125:2405-17.

Manca L, Masala B. Disorders of the Synthesis of Human Fetal Hemoglobin, IUBMB Life 2008; 60:94-111.

Nagel RL. Disorder of Hemoglobin Function and Stability. Handin R I, Lux S E and Stossel T P. Blood: Principles and Practice of Hematology. Philadelpphia: Lippincott Williams&Wilkins, 2003, pp. 1597-1654.

Pereira C, Relvas L, Bento C, Abade A, Ribeiro ML, Manco L. Polymorphic variations influencing fetal hemoglobin levels: Association study in beta-thalassemia carriers and in normal individuals of Portuguese origin. Blood Cells Mol Dis 2015; 54:315–20.

Radmilovic M, Zukic B, Petrovic MS, Bartsakoulia M, Stankovic B, Kotur N, Dokmanovic L, Georgitsi M, Patrinos GP, Pavlovic S. Functional analysis of a novel KLF1 gene promoter variation associated with hereditary persistence of fetal hemoglobin. Ann Hematol 2013; 92:53-8.

Rochette J, Craig JE, Thein SL. Fetal Hemoglobin Levels in Adults. Blood Rev 1994; 8:213-24.

Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudine M, Bender MA, Tucker PW, Orkin SH. Developmental and species-divergent globin switching are driven by BCL11A. Nature 2009; 460:1093-7.

Shariati L, Khanahmad H, Salehi M, Hejazi Z, Rahimmanesh I, Tabatabaiefar MA, Modarressi MH. Genetic disruption of the KLF1 gene to overexpress the Î³-globin gene using the CRISPR/Cas9 system. J Gene Med 2016; 18:294-301.

Stoming TA, Stoming GS, Lanclos KD, Fei YJ, Altay C, Kutlar F, Huisman THJ. An AÎ³ type of nondeletional hereditary persistence of fetal hemoglobin with a Tâ†’C mutation at position –175 to the cap site of the AÎ³ globin gene. Blood 1989; 73:329-33.

Åžişli N. Vücut Proteinleri ve Fonksiyonları. Onat T, Emerk K, Sözmen e Y. ć°nsan biyokimyası. Ankara: Palme yayıncılık, 2002, pp. 135-44.

Tasiopoulou M, Boussiou M, Sinopoulou K, Moraitis G, Loutradi-Anagnostou A, Karababa P. G gamma-196 C-->T, A gamma-201 C-->T: two novel mutations in the promoter region of the gamma-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece. Blood Cells Mol Dis 2008; 40:320-2.

Thompson M, Mcinnes RR, Willard HF. Genetics in Medicine. 5th ed., Philadelphia: B. Saunders Comp., 1991, pp. 247-70.

Vinjamur DS, Wade KJ, Mohamad SF, Haar JL, Sawyer ST, Lloyd JA. Krüppel-like transcription factors KLF1 and KLF2 have unique and coordinate roles in regulating embryonic erythroid precursor maturation. Haematologica 2014; 99:1565-73.

Wang T, He Y, Zhou JY, Xie XM, Li J, Li R, Liao C, Li DZ. KLF1 gene mutations in Chinese adults with increased fetal hemoglobin. Hemoglobin 2013; 37:501-6.

Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th. Ed., Blackwell science, 2001, pp. 64-120.

Author biographies is not available.