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BioMed Research International
Volume 2015, Article ID 278536, 9 pages
http://dx.doi.org/10.1155/2015/278536
Review Article

Biology of Heme in Mammalian Erythroid Cells and Related Disorders

1Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
2Molecular Hematology/Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

Received 11 April 2015; Accepted 14 June 2015

Academic Editor: Aurora M. Cianciarullo

Copyright © 2015 Tohru Fujiwara and Hideo Harigae. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. K. Furuyama, K. Kaneko, and P. D. Vargas, “Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis,” The Tohoku Journal of Experimental Medicine, vol. 213, no. 1, pp. 1–16, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. S. Sassa, “Modern diagnosis and management of the porphyrias,” British Journal of Haematology, vol. 135, no. 3, pp. 281–292, 2006. View at Publisher · View at Google Scholar · View at Scopus
  3. D. Chiabrando, S. Mercurio, and E. Tolosano, “Heme and erythropoieis: more than a structural role,” Haematologica, vol. 99, no. 6, pp. 973–983, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. H. A. Dailey and P. N. Meissner, “Erythroid heme biosynthesis and its disorders,” Cold Spring Harbor Perspectives in Medicine, vol. 3, no. 4, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Chung, C. Chen, and B. H. Paw, “Heme metabolism and erythropoiesis,” Current Opinion in Hematology, vol. 19, no. 3, pp. 156–162, 2012. View at Publisher · View at Google Scholar · View at Scopus
  6. P. D. Cotter, H. A. Drabkin, T. Varkony, D. I. Smith, and D. F. Bishop, “Assignment of the human housekeeping δ-aminolevulinate synthase gene (ALAS1) to chromosome band 3p21.1 by PCR analysis of somatic cell hybrids,” Cytogenetics and Cell Genetics, vol. 69, no. 3-4, pp. 207–208, 1995. View at Publisher · View at Google Scholar · View at Scopus
  7. P. D. Cotter, H. F. Willard, J. L. Gorski, and D. F. Bishop, “Assignment of human erythroid δ-aminolevulinate synthase (ALAS2) to a distal subregion of band Xp11.21 by PCR analysis of somatic cell hybrids containing X; Autosome translocations,” Genomics, vol. 13, no. 1, pp. 211–212, 1992. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Fujiwara, H. O'Geen, S. Keles et al., “Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy,” Molecular Cell, vol. 36, no. 4, pp. 667–681, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. K. Kaneko, K. Furuyama, T. Fujiwara et al., “Identification of a novel erythroid-specific enhancer for the ALAS2 gene and its loss-of-function mutation which is associated with congenital sideroblastic anemia,” Haematologica, vol. 99, no. 2, pp. 252–261, 2014. View at Publisher · View at Google Scholar · View at Scopus
  10. P. T. Erskine, N. Senior, S. Awan et al., “X-ray structure of 5-aminolaevulinate dehydratase, a hybrid aldolase,” Nature Structural Biology, vol. 4, no. 12, pp. 1025–1031, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. A. H. Kaya, M. Plewinska, D. M. Wong, R. J. Desnick, and J. G. Wetmur, “Human δ-aminolevulinate dehydratase (ALAD) gene: structure and alternative splicing of the erythroid and housekeeping mRNAs,” Genomics, vol. 19, no. 2, pp. 242–248, 1994. View at Publisher · View at Google Scholar · View at Scopus
  12. Y. Y. Yien, R. F. Robledo, I. J. Schultz et al., “TMEM14C is required for erythroid mitochondrial heme metabolism,” Journal of Clinical Investigation, vol. 124, no. 10, pp. 4294–4304, 2014. View at Publisher · View at Google Scholar
  13. T. Fujiwara and H. Harigae, “Pathophysiology and genetic mutations in congenital sideroblastic anemia,” Pediatrics International, vol. 55, no. 6, pp. 675–679, 2013. View at Publisher · View at Google Scholar · View at Scopus
  14. T. Fujiwara and H. Harigae, “Update on the biology of heme synthesis in erythroid cells,” Rinsho Ketsueki, vol. 56, no. 2, pp. 119–127, 2015. View at Publisher · View at Google Scholar
  15. C.-K. Wu, H. A. Dailey, J. P. Rose, A. Burden, V. M. Sellers, and B.-C. Wang, “The 2.0 Å structure of human ferrochelatase, the terminal enzyme of heme biosynthesis,” Nature Structural & Molecular Biology, vol. 8, no. 2, pp. 156–160, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. A. Tugores, S. T. Magness, and D. A. Brenner, “A single promoter directs both housekeeping and erythroid preferential expression of the human ferrochelatase gene,” The Journal of Biological Chemistry, vol. 269, no. 49, pp. 30789–30797, 1994. View at Google Scholar · View at Scopus
  17. R. S. Ohgami, D. R. Campagna, E. L. Greer et al., “Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells,” Nature Genetics, vol. 37, no. 11, pp. 1264–1269, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. G. C. Shaw, J. J. Cope, L. Li et al., “Mitoferrin is essential for erythroid iron assimilation,” Nature, vol. 440, no. 7080, pp. 96–100, 2006. View at Publisher · View at Google Scholar · View at Scopus
  19. W. Chen, P. N. Paradkar, L. Li et al., “Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 38, pp. 16263–16268, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. M. D. Fleming, “Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation,” Hematology/the Education Program of the American Society of Hematology, vol. 2011, pp. 525–531, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. D. L. Guernsey, H. Jiang, D. R. Campagna et al., “Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia,” Nature Genetics, vol. 41, no. 6, pp. 651–653, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. T. Fujiwara, K. Okamoto, R. Niikuni et al., “Effect of 5-aminolevulinic acid on erythropoiesis: a preclinical in vitro characterization for the treatment of congenital sideroblastic anemia,” Biochemical and Biophysical Research Communications, vol. 454, no. 1, pp. 102–108, 2014. View at Publisher · View at Google Scholar
  23. P. C. Krishnamurthy, G. Du, Y. Fukuda et al., “Identification of a mammalian mitochondrial porphyrin transporter,” Nature, vol. 443, no. 7111, pp. 586–589, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Krishnamurthy and J. D. Schuetz, “The role of ABCG2 and ABCB6 in porphyrin metabolism and cell survival,” Current Pharmaceutical Biotechnology, vol. 12, no. 4, pp. 647–655, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. J. K. Paterson, S. Shukla, C. M. Black et al., “Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane,” Biochemistry, vol. 46, no. 33, pp. 9443–9452, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Tsuchida, Y. Emi, Y. Kida, and M. Sakaguchi, “Human ABC transporter isoform B6 (ABCB6) localizes primarily in the Golgi apparatus,” Biochemical and Biophysical Research Communications, vol. 369, no. 2, pp. 369–375, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. K. Kiss, A. Brozik, N. Kucsma et al., “Shifting the paradigm: the putative mitochondrial protein ABCB6 resides in the lysosomes of cells and in the plasma membrane of erythrocytes,” PLoS ONE, vol. 7, no. 5, Article ID e37378, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. V. Helias, C. Saison, B. A. Ballif et al., “ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis,” Nature Genetics, vol. 44, no. 2, pp. 170–173, 2012. View at Publisher · View at Google Scholar · View at Scopus
  29. L. Wang, F. He, J. Bu et al., “ABCB6 mutations cause ocular coloboma,” The American Journal of Human Genetics, vol. 90, no. 1, pp. 40–48, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Liu, Y. Li, K. K. Hung et al., “Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria,” PLoS ONE, vol. 9, no. 2, Article ID e87250, 2014. View at Publisher · View at Google Scholar
  31. R. Nilsson, I. J. Schultz, E. L. Pierce et al., “Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis,” Cell Metabolism, vol. 10, no. 2, pp. 119–130, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. J. G. Quigley, Z. Yang, M. T. Worthington et al., “Identification of a human heme exporter that is essential for erythropoiesis,” Cell, vol. 118, no. 6, pp. 757–766, 2004. View at Publisher · View at Google Scholar · View at Scopus
  33. S. B. Keel, R. T. Doty, Z. Yang et al., “A heme export protein is required for red blood cell differentiation and iron homeostasis,” Science, vol. 319, no. 5864, pp. 825–828, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. D. Chiabrando, S. Marro, S. Mercurio et al., “The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation,” Journal of Clinical Investigation, vol. 122, no. 12, pp. 4569–4579, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. S. P. Duffy, J. Shing, P. Saraon et al., “The Fowler syndrome-associated protein FLVCR2 is an importer of heme,” Molecular and Cellular Biology, vol. 30, no. 22, pp. 5318–5324, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. J. T. Lathrop and M. P. Timko, “Regulation by heme of mitochondrial protein transport through a conserved amino acid motif,” Science, vol. 259, no. 5094, pp. 522–525, 1993. View at Publisher · View at Google Scholar · View at Scopus
  37. K. Igarashi and M. Watanabe-Matsui, “Wearing red for signaling: the heme-bach axis in heme metabolism, oxidative stress response and iron immunology,” The Tohoku Journal of Experimental Medicine, vol. 232, no. 4, pp. 229–253, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. H. Harigae, T. Fujiwara, and K. Furuyama, “Heme metabolism and anemia,” Rinsho Ketsueki, vol. 55, no. 7, pp. 729–734, 2014. View at Google Scholar
  39. T. Oyake, K. Itoh, H. Motohashi et al., “Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site,” Molecular and Cellular Biology, vol. 16, no. 11, pp. 6083–6095, 1996. View at Google Scholar · View at Scopus
  40. K. Ogawa, J. Sun, S. Taketani et al., “Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1,” The EMBO Journal, vol. 20, no. 11, pp. 2835–2843, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. H. Suzuki, S. Tashiro, S. Hira et al., “Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1,” The EMBO Journal, vol. 23, no. 13, pp. 2544–2553, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. Y. Zenke-Kawasaki, Y. Dohi, Y. Katoh et al., “Heme induces ubiquitination and degradation of the transcription factor Bach1,” Molecular and Cellular Biology, vol. 27, no. 19, pp. 6962–6971, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Tahara, J. Sun, K. Nakanishi et al., “Heme positively regulates the expression of β-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells,” The Journal of Biological Chemistry, vol. 279, no. 7, pp. 5480–5487, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. J. Sun, M. Brand, Y. Zenke, S. Tashiro, M. Groudine, and K. Igarashi, “Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 6, pp. 1461–1466, 2004. View at Publisher · View at Google Scholar · View at Scopus
  45. S. Marro, D. Chiabrando, E. Messana et al., “Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter,” Haematologica, vol. 95, pp. 1261–1268, 2010. View at Google Scholar
  46. K. J. Hintze, Y. Katoh, K. Igarashi, and E. C. Theil, “Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, β-globin, and NADP(H) quinone (Oxido) reductase1,” The Journal of Biological Chemistry, vol. 282, no. 47, pp. 34365–34371, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Haldar, M. Kohyama, A. Y.-L. So et al., “Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages,” Cell, vol. 156, no. 6, pp. 1223–1234, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Reinking, M. M. S. Lam, K. Pardee et al., “The Drosophila nuclear receptor E75 contains heme and is gas responsive,” Cell, vol. 122, no. 2, pp. 195–207, 2005. View at Publisher · View at Google Scholar · View at Scopus
  49. N. Wu, L. Yin, E. A. Hanniman, S. Joshi, and M. A. Lazar, “Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbα,” Genes & Development, vol. 23, no. 18, pp. 2201–2209, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. J.-J. Chen, M. S. Throop, L. Gehrke et al., “Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2α (eIF-2α) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2α kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 17, pp. 7729–7733, 1991. View at Publisher · View at Google Scholar · View at Scopus
  51. B. N. Bauer, M. Rafie-Kolpin, L. Lu, A. Han, and J.-J. Chen, “Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2α kinase,” Biochemistry, vol. 40, no. 38, pp. 11543–11551, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Rafie-Kolpin, A.-P. Han, and J.-J. Chen, “Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2α kinase activity of HRI,” Biochemistry, vol. 42, no. 21, pp. 6536–6544, 2003. View at Publisher · View at Google Scholar · View at Scopus
  53. J.-J. Chen, “Translational control by heme-regulated eIF2α kinase during erythropoiesis,” Current Opinion in Hematology, vol. 21, no. 3, pp. 172–178, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. A.-P. Han, C. Yu, L. Lu et al., “Heme-regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency,” The EMBO Journal, vol. 20, no. 23, pp. 6909–6918, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. A.-P. Han, M. D. Fleming, and J.-J. Chen, “Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia,” The Journal of Clinical Investigation, vol. 115, no. 6, pp. 1562–1570, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. T.-W. Yu and D. Anderson, “Reactive oxygen species-induced DNA damage and its modification: a chemical investigation,” Mutation Research, vol. 379, no. 2, pp. 201–210, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. N. Wilkinson and K. Pantopoulos, “The IRP/IRE system in vivo: insights from mouse models,” Frontiers in Pharmacology, vol. 5, article 176, 2014. View at Publisher · View at Google Scholar
  58. E. G. Meyron-Holtz, M. C. Ghosh, and T. A. Rouault, “Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo,” Science, vol. 306, no. 5704, pp. 2087–2090, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. K. Iwai, R. D. Klausner, and T. A. Rouault, “Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2,” The EMBO Journal, vol. 14, no. 21, pp. 5350–5357, 1995. View at Google Scholar · View at Scopus
  60. K. Iwai, S. K. Drake, N. B. Wehr et al., “Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 9, pp. 4924–4928, 1998. View at Publisher · View at Google Scholar · View at Scopus
  61. L.-L. Chen and G. G. Carmichael, “Long noncoding RNAs in mammalian cells: what, where, and why?” Wiley Interdisciplinary Reviews: RNA, vol. 1, no. 1, pp. 2–21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  62. D. P. Bartel, “MicroRNAs: target recognition and regulatory functions,” Cell, vol. 136, no. 2, pp. 215–233, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Faller, M. Matsunaga, S. Yin, J. A. Loo, and F. Guo, “Heme is involved in microRNA processing,” Nature Structural & Molecular Biology, vol. 14, no. 1, pp. 23–29, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. I. Barr, A. T. Smith, Y. Chen, R. Senturia, J. N. Burstyn, and F. Guo, “Ferric, not ferrous, heme activates RNA-binding protein DGCR8 for primary microRNA processing,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 6, pp. 1919–1924, 2012. View at Publisher · View at Google Scholar · View at Scopus
  65. L. Zhang, V. G. Sankaran, and H. F. Lodish, “MicroRNAs in erythroid and megakaryocytic differentiation and megakaryocyte-erythroid progenitor lineage commitment,” Leukemia, vol. 26, no. 11, pp. 2310–2316, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. P. Ponka and J. T. Prchal, “Hereditary and acquired sideroblastic anemias,” in Wiiliams Hematology, pp. 865–881, McGraw-Hill, 8th edition, 2010. View at Google Scholar
  67. H. Harigae and K. Furuyama, “Hereditary sideroblastic anemia: pathophysiology and gene mutations,” International Journal of Hematology, vol. 92, no. 3, pp. 425–431, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. K. Yoshida, M. Sanada, Y. Shiraishi et al., “Frequent pathway mutations of splicing machinery in myelodysplasia,” Nature, vol. 478, no. 7367, pp. 64–69, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Camaschella, “Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment,” Seminars in Hematology, vol. 46, no. 4, pp. 371–377, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. P. K. Chakraborty, K. Schmitz-Abe, E. K. Kennedy et al., “Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD),” Blood, vol. 124, no. 18, pp. 2867–2871, 2014. View at Publisher · View at Google Scholar
  71. A. E. Donker, R. A. Raymakers, L. T. Vlasveld et al., “Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis,” Blood, vol. 123, no. 25, pp. 3873–3886, 2014. View at Publisher · View at Google Scholar
  72. B. Grandchamp, G. Hetet, C. Kannengiesser et al., “A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene,” Blood, vol. 118, no. 25, pp. 6660–6666, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. H. Harigae, N. Suwabe, P. H. Weinstock et al., “Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific δ-aminolevulinate synthase gene,” Blood, vol. 91, no. 3, pp. 798–805, 1998. View at Google Scholar · View at Scopus
  74. K. Furuyama, H. Harigae, C. Kinoshita et al., “Late-onset X-linked sideroblastic anemia following hemodialysis,” Blood, vol. 101, no. 11, pp. 4623–4624, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. N. Rollón, M. C. Fernández-Jiménez, M. I. Moreno-Carralero, M. J. Murga-Fernández, and M. J. Morán-Jiménez, “Microcytic anemia in a pregnant woman: beyond iron deficiency,” International Journal of Hematology, vol. 101, no. 5, pp. 514–519, 2015. View at Publisher · View at Google Scholar
  76. E. Aguiar, M. I. Freitas, and J. Barbot, “Different haematological picture of congenital sideroblastic anaemia in a hemizygote and a heterozygote,” British Journal of Haematology, vol. 166, no. 4, p. 469, 2014. View at Publisher · View at Google Scholar
  77. K. Furuyama and S. Sassa, “Multiple mechanisms for hereditary sideroblastic anemia,” Cellular and Molecular Biology, vol. 48, no. 1, pp. 5–10, 2002. View at Google Scholar · View at Scopus
  78. A. K. Bergmann, D. R. Campagna, E. M. McLoughlin et al., “Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations,” Pediatric Blood & Cancer, vol. 54, no. 2, pp. 273–278, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. S. Bekri, A. May, P. D. Cotter et al., “A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia,” Blood, vol. 102, no. 2, pp. 698–704, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. D. R. Campagna, C. I. de Bie, K. Schmitz-Abe et al., “X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations,” American Journal of Hematology, vol. 89, pp. 315–319, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. T. C. Cox, S. S. Bottomley, J. S. Wiley, M. J. Bawden, C. S. Matthews, and B. K. May, “X-linked pyridoxine-responsive sideroblastic anemia due to a THR388-TO-SER substitution in erythroid 5-aminolevulinate synthase,” The New England Journal of Medicine, vol. 330, no. 10, pp. 675–679, 1994. View at Publisher · View at Google Scholar · View at Scopus
  82. R. Ohba, K. Furuyama, K. Yoshida et al., “Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS),” Annals of Hematology, vol. 92, no. 1, pp. 1–9, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. M. Ishizuka, F. Abe, Y. Sano et al., “Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy,” International Immunopharmacology, vol. 11, no. 3, pp. 358–365, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Balwani and R. J. Desnick, “The porphyrias: advances in diagnosis and treatment,” Hematology, vol. 2012, pp. 19–27, 2012. View at Google Scholar · View at Scopus
  85. S. A. Holme, M. Worwood, A. V. Anstey, G. H. Elder, and M. N. Badminton, “Erythropoiesis and iron metabolism in dominant erythropoietic protoporphyria,” Blood, vol. 110, no. 12, pp. 4108–4110, 2007. View at Publisher · View at Google Scholar · View at Scopus
  86. L. H. P. M. Rademakers, J. C. Koningsberger, C. W. J. Sorber, H. B. de la Faille, J. van Hattum, and J. J. M. Marx, “Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria,” European Journal of Clinical Investigation, vol. 23, no. 2, pp. 130–138, 1993. View at Publisher · View at Google Scholar · View at Scopus
  87. A. A. Lamola, S. Piomelli, M. B. P. Fitzpatrick, T. Yamane, and L. C. Harber, “Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. II. Different binding of erythrocyte protoporphyrin to hemoglobin,” The Journal of Clinical Investigation, vol. 56, no. 6, pp. 1528–1535, 1975. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Gouya, H. Puy, A.-M. Robreau et al., “The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH,” Nature Genetics, vol. 30, no. 1, pp. 27–28, 2002. View at Publisher · View at Google Scholar · View at Scopus
  89. L. Gouya, C. Martin-Schmitt, A.-M. Robreau et al., “Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria,” The American Journal of Human Genetics, vol. 78, no. 1, pp. 2–14, 2006. View at Publisher · View at Google Scholar · View at Scopus
  90. E. I. Minder and X. Schneider-Yin, “Afamelanotide (CUV1647) in dermal phototoxicity of erythropoietic protoporphyria,” Expert Review of Clinical Pharmacology, vol. 8, no. 1, pp. 43–53, 2015. View at Publisher · View at Google Scholar
  91. D. P. Bentley and E. M. Meek, “Clinical and biochemical improvement following low-dose intravenous iron therapy in a patient with erythropoietic protoporphyria,” British Journal of Haematology, vol. 163, no. 2, pp. 289–291, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. S. D. Whatley, S. Ducamp, L. Gouya et al., “C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload,” The American Journal of Human Genetics, vol. 83, no. 3, pp. 408–414, 2008. View at Publisher · View at Google Scholar · View at Scopus
  93. S. S. Cooperman, E. G. Meyron-Holtz, H. Olivierre-Wilson, M. C. Ghosh, J. P. McConnell, and T. A. Rouault, “Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2,” Blood, vol. 106, no. 3, pp. 1084–1091, 2005. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Balwani, D. Doheny, D. F. Bishop et al., “Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria,” Molecular Medicine, vol. 19, no. 1, pp. 26–35, 2013. View at Publisher · View at Google Scholar · View at Scopus
  95. J. To-Figueras, S. Ducamp, J. Clayton et al., “ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria,” Blood, vol. 118, no. 6, pp. 1443–1451, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. E. Di Pierro, R. Russo, Z. Karakas et al., “Congenital erythropoietic porphyria linked to GATA1-R216W mutation: challenges for diagnosis,” European Journal of Haematology, vol. 94, no. 6, pp. 491–497, 2015. View at Publisher · View at Google Scholar