Heme and erythropoieis: More than a structural role

Haematologica

Volumn 99, Issue 6, 2014, Pages 973-983

  Chiabrando, Deborah ^a   Mercurio, Sonia ^a   Tolosano, Emanuela ^a  

^a UNIVERSITY OF TURIN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ABCB10 PROTEIN; AMINOLEVULINIC ACID; CARRIER PROTEIN; GLUTAREDOXIN; HEME; MEMBRANE PROTEIN; MESSENGER RNA; SOLUTE CARRIER FAMILY 25 MEMBER 38 PROTEIN; UNCLASSIFIED DRUG;

ALAS2 GENE; ATAXIA; CONGENITAL ERYTHROPOIETIC PORPHYRIA; CPOX GENE; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; ERYTHROPOIETIC PROTOPORPHYRIA; FLVCR1 GENE; GENE; GENE EXPRESSION; GENE MUTATION; GENE OVEREXPRESSION; GENETIC TRANSCRIPTION; HARDEROPORPHYRIA; HEME SYNTHESIS; HEPATOERYTHROPOIETIC PORPHYRIA; HUMAN; IRON METABOLISM; MITOCHONDRIAL MEMBRANE; MITOCHONDRION; OXIDATIVE STRESS; PATHOGENESIS; PHENOTYPE; PORPHYRIA; PROTEIN SYNTHESIS; REVIEW; SIDEROBLASTIC ANEMIA; UROS GENE; X LINKED SIDEROBLASTIC ANEMIA; ANIMAL; BIOSYNTHESIS; CELL DIFFERENTIATION; CHEMISTRY; CYTOLOGY; ERYTHROCYTE; GENE EXPRESSION REGULATION; GENETICS; HEMATOLOGIC DISEASE; METABOLISM; PHYSIOLOGY;

ANIMALS; BIOSYNTHETIC PATHWAYS; CELL DIFFERENTIATION; ERYTHROCYTES; ERYTHROPOIESIS; GENE EXPRESSION REGULATION; HEMATOLOGIC DISEASES; HEME; HUMANS; MITOCHONDRIA;

EID: 84901721544     PISSN: 03906078     EISSN: 15928721     Source Type: Journal    
DOI: 10.3324/haematol.2013.091991     Document Type: Review

References (99)

1. Bishop DF, Henderson AS, Astrin KH. Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome. Genomics. 1990;7(2):207-14.
2. Harigae H, Suwabe N, Weinstock PH, Nagai M, Fujita H, Yamamoto M, et al. Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific delta-aminolevulinate synthase gene. Blood. 1998;91(3):798-805.
3. Sadlon TJ, Dell'Oso T, Surinya KH, May BK. Regulation of erythroid 5-aminolevulinate synthase expression during erythropoiesis. Int J Biochem Cell Biol. 1999;31(10):1153-67.
4. Kaneko K, Furuyama K, Fujiwara T, Kobayashi R, Ishida H, Harigae H, et al. Identification of the novel erythroid-specific enhancer for ALAS2 gene and its loss-offunction mutation associated with congenital sideroblastic anemia. Haematologica. 2014;99(2):252-61.
5. Surinya KH, Cox TC, May BK. Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene. J Biol Chem. 1998;273(27): 16798-809.
6. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117 (3):285-97.
7. Ajioka RS, Phillips JD, Kushner JP. Biosynthesis of heme in mammals. Biochim Biophys Acta. 2006;1763(7):723-36.
8. Tugores A, Magness ST, Brenner DA. A single promoter directs both housekeeping and erythroid preferential expression of the human ferrochelatase gene. J Biol Chem. 1994;269(49):30789-97.
9. Crooks DR, Ghosh MC, Haller RG, Tong WH, Rouault TA. Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood. 2010;115(4):860-9.
10. Shi H, Bencze KZ, Stemmler TL, Philpott CC. A cytosolic iron chaperone that delivers iron to ferritin. Science. 2008;320(5880): 1207-10.
11. Vaisman B, Fibach E, Konijn AM. Utilization of intracellular ferritin iron for hemoglobin synthesis in developing human erythroid precursors. Blood. 1997;90(2):831-8.
12. Sheftel AD, Zhang AS, Brown C, Shirihai OS, Ponka P. Direct interorganellar transfer of iron from endosome to mitochondrion. Blood. 2007;110(1):125-32.
13. Paradkar PN, Zumbrennen KB, Paw BH, Ward DM, Kaplan J. Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2. Mol Cell Biol. 2009;29(4):1007-16.
14. Shaw GC, Cope JJ, Li L, Corson K, Hersey C, Ackermann GE, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440(7080):96-100.
15. Hamza I, Dailey HA. One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans. Biochim Biophys Acta. 2012;1823(9):1617-32.
16. Chen W, Dailey HA, Paw BH. Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood. 2010;116(4):628-30.
17. Chen W, Paradkar PN, Li L, Pierce EL, Langer NB, Takahashi-Makise N, et al. Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proc Natl Acad Sci USA. 2009;106(38):16263-8.
18. Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 2004;447(5): 689-709.
19. Guernsey DL, Jiang H, Campagna DR, Evans SC, Ferguson M, Kellogg MD, et al. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet. 2009;41(6):651-3.
20. Graf SA, Haigh SE, Corson ED, Shirihai OS. Targeting, import, and dimerization of a mammalian mitochondrial ATP binding cassette (ABC) transporter, ABCB10 (ABC-me). J Biol Chem. 2004;279(41):42954-63.
21. Shirihai OS, Gregory T, Yu C, Orkin SH, Weiss MJ. ABC-me: a novel mitochondrial transporter induced by GATA-1 during erythroid differentiation. EMBO J. 2000;19(11): 2492-502.
22. Tang L, Bergevoet SM, Bakker-Verweij G, Harteveld CL, Giordano PC, Nijtmans L, et al. Human mitochondrial ATP-binding cassette transporter ABCB10 is required for efficient red blood cell development. Br J Haematol. 2011;157(1):151-4.
23. Hyde BB, Liesa M, Elorza AA, Qiu W, Haigh SE, Richey L, et al. The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo. Cell Death Differ. 2012;19 (7):1117-26.
24. Bayeva M, Khechaduri A, Wu R, Burke MA, Wasserstrom JA, Singh N, et al. ABCB10 Regulates Early Steps of Heme Synthesis. Circ Res. 2013;113(3):279-87.
25. Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006;443(7111):586-9.
26. Tsuchida M, Emi Y, Kida Y, Sakaguchi M. Human ABC transporter isoform B6 (ABCB6) localizes primarily in the Golgi apparatus. Biochem Biophys Res Commun. 2008;369(2):369-75.
27. Paterson JK, Shukla S, Black CM, Tachiwada T, Garfield S, Wincovitch S, et al. Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane. Biochemistry. 2007;46(33):9443-52.
28. Kiss K, Brozik A, Kucsma N, Toth A, Gera M, Berry L, 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. 2012;7(5):e37378.
29. Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH, et al. Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate. PLoS One. 2007;2(8):e798.
30. Helias V, Saison C, Ballif BA, Peyrard T, Takahashi J, Takahashi H, et al. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet. 2012;44(2):170-3.
31. Wang L, He F, Bu J, Zhen Y, Liu X, Du W, et al. ABCB6 mutations cause ocular coloboma. Am J Hum Genet. 2012;90(1):40-8.
32. Ulrich DL, Lynch J, Wang Y, Fukuda Y, Nachagari D, Du G, et al. ATP-dependent mitochondrial porphyrin importer ABCB6 protects against phenylhydrazine toxicity. J Biol Chem. 2012;287(16):12679-90.
33. Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, et al. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J Clin Invest. 2012; 122(12):4569-79.
34. Fleming MD, Hamza I. Mitochondrial heme: an exit strategy at last. J Clin Invest. 2012;122(12):4328-30.
35. Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell. 2004;118(6):757-66.
36. Keel SB, Doty RT, Yang Z, Quigley JG, Chen J, Knoblaugh S, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319 (5864):825-8.
37. Law CJ, Maloney PC, Wang DN. Ins and outs of major facilitator superfamily antiporters. Annu Rev Microbiol. 2008;62: 289-305.
38. Pao SS, Paulsen IT, Saier MH Jr. Major facilitator superfamily. Microbiol Mol Biol Rev. 1998;62(1):1-34.
39. Vinchi F, Ingoglia G, Chiabrando D, Mercurio S, Turco E, Silengo L, et al. The Heme Exporter FLVCR1a Regulates Heme Synthesis and Degradation and Controls Activity of Cytochromes P450. Gastroenterology. 2014;146(5):1325-38.
40. Sinclair J, Hamza I. A novel heme-responsive element mediates transcriptional regulation in Caenorhabditis elegans. J Biol Chem. 2010;285(50):39536-43.
41. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood. 2007;109(7):2693-9.
42. Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microRNA processing. Nat Struct Mol Biol. 2007;14(1):23-9.
43. Barr I, Smith AT, Chen Y, Senturia R, Burstyn JN, Guo F. Ferric, not ferrous, heme activates RNA-binding protein DGCR8 for primary microRNA processing. Proc Natl Acad Sci USA. 2012;109(6):1919-24.
44. Munakata H, Sun JY, Yoshida K, Nakatani T, Honda E, Hayakawa S, et al. Role of the heme regulatory motif in the heme-mediated inhibition of mitochondrial import of 5-aminolevulinate synthase. J Biochem. 2004;136(2):233-8.
45. Yamamoto M, Hayashi N, Kikuchi G. Evidence for the transcriptional inhibition by heme of the synthesis of delta-aminolevulinate synthase in rat liver. Biochem Biophys Res Commun. 1982;105(3):985-90.
46. Yamamoto M, Hayashi N, Kikuchi G. Translational inhibition by heme of the synthesis of hepatic delta-aminolevulinate synthase in a cell-free system. Biochem Biophys Res Commun. 1983;115(1):225-31.
47. Kramer MF, Gunaratne P, Ferreira GC. Transcriptional regulation of the murine erythroid-specific 5-aminolevulinate synthase gene. Gene. 2000;247(1-2):153-66.
48. Yamanaka K, Ishikawa H, Megumi Y, Tokunaga F, Kanie M, Rouault TA, et al. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol. 2003;5(4):336-40.
49. Ishikawa H, Kato M, Hori H, Ishimori K, Kirisako T, Tokunaga F, et al. Involvement of heme regulatory motif in heme-mediated ubiquitination and degradation of IRP2. Mol Cell. 2005;19(2):171-81.
50. Reichard JF, Motz GT, Puga A. Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1. Nucleic Acids Res. 2007;35(21):7074-86.
51. Hintze KJ, Katoh Y, Igarashi K, Theil EC. Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1. J Biol Chem. 2007;282(47):34365-71.
52. Tahara T, Sun J, Igarashi K, Taketani S. Heme-dependent up-regulation of the alpha-globin gene expression by transcriptional repressor Bach1 in erythroid cells. Biochem Biophys Res Commun. 2004;324 (1):77-85.
53. Tahara T, Sun J, Nakanishi K, Yamamoto M, Mori H, Saito T, et al. Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells. J Biol Chem. 2004;279(7):5480-7.
54. Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, et al. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position-7007 of the FPN1 promoter. Haematologica. 2010;95(8):1261-8.
55. Ogawa K, Sun J, Taketani S, Nakajima O, Nishitani C, Sassa S, et al. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 2001;20(11):2835-43.
56. Suzuki H, Tashiro S, Hira S, Sun J, Yamazaki C, Zenke Y, et al. Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J. 2004;23(13):2544-53.
57. Zenke-Kawasaki Y, Dohi Y, Katoh Y, Ikura T, Ikura M, Asahara T, et al. Heme induces ubiquitination and degradation of the transcription factor Bach1. Mol Cell Biol. 2007;27(19):6962-71.
58. Nguyen T, Yang CS, Pickett CB. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med. 2004;37(4):433-41.
59. Eggler AL, Liu G, Pezzuto JM, van Breemen RB, Mesecar AD. Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci USA. 2005;102(29):10070-5.
60. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236(2):313-22.
61. Crosby JS, Lee K, London IM, Chen JJ. Erythroid expression of the heme-regulated eIF-2 alpha kinase. Mol Cell Biol. 1994;14 (6):3906-14.
62. Han AP, Yu C, Lu L, Fujiwara Y, Browne C, Chin G, et al. Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J. 2001;20(23): 6909-18.
63. Han AP, Fleming MD, Chen JJ. Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest. 2005;115(6):1562-70.
64. Masuoka HC, Townes TM. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood. 2002;99(3):736-45.
65. Suragani RN, Zachariah RS, Velazquez JG, Liu S, Sun CW, Townes TM, et al. Hemeregulated eIF2alpha kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood. 2012;119(22):5276-84.
66. Fleming MD. Congenital sideroblastic anemias: iron and heme lost in mitochondrial translation. Hematology Am Soc Hematol Educ Program. 2011;2011:525-31.
67. Camaschella C, Poggiali E. Inherited disorders of iron metabolism. Curr Opin Pediatr. 2011;23(1):14-20.
68. Sheftel AD, Richardson DR, Prchal J, Ponka P. Mitochondrial iron metabolism and sideroblastic anemia. Acta Haematol. 2009;122 (2-3):120-33.
69. Nakajima O, Takahashi S, Harigae H, Furuyama K, Hayashi N, Sassa S, et al. Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload. EMBO J. 1999;18(22):6282-9.
70. Brownlie A, Donovan A, Pratt SJ, Paw BH, Oates AC, Brugnara C, et al. Positional cloning of the zebrafish sauternes gene: a model for congenital sideroblastic anaemia. Nat Genet. 1998;20(3):244-50.
71. Pondarre C, Antiochos BB, Campagna DR, Clarke SL, Greer EL, Deck KM, et al. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. Hum Mol Genet. 2006;15(6):953-64.
72. Clarke SL, Vasanthakumar A, Anderson SA, Pondarre C, Koh CM, Deck KM, et al. Ironresponsive degradation of iron-regulatory protein 1 does not require the Fe-S cluster. EMBO J. 2006;25(3):544-53.
73. Wingert RA, Galloway JL, Barut B, Foott H, Fraenkel P, Axe JL, et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature. 2005;436(7053):1035-9.
74. Tutois S, Montagutelli X, Da Silva V, Jouault H, Rouyer-Fessard P, Leroy-Viard K, et al. Erythropoietic protoporphyria in the house mouse. A recessive inherited ferrochelatase deficiency with anemia, photosensitivity, and liver disease. J Clin Invest. 1991;88(5): 1730-6.
75. Magness ST, Maeda N, Brenner DA. An exon 10 deletion in the mouse ferrochelatase gene has a dominant-negative effect and causes mild protoporphyria. Blood. 2002;100(4):1470-7.
76. Childs S, Weinstein BM, Mohideen MA, Donohue S, Bonkovsky H, Fishman MC. Zebrafish dracula encodes ferrochelatase and its mutation provides a model for erythropoietic protoporphyria. Curr Biol. 2000;10(16):1001-4.
77. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of ironregulatory protein 2. Blood. 2005;106(3): 1084-91.
78. Bishop DF, Johansson A, Phelps R, Shady AA, Ramirez MC, Yasuda M, et al. Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions. Am J Hum Genet. 2006;78(4):645-58.
79. Ged C, Mendez M, Robert E, Lalanne M, Lamrissi-Garcia I, Costet P, et al. A knock-in mouse model of congenital erythropoietic porphyria. Genomics. 2006;87(1):84-92.
80. Phillips JD, Jackson LK, Bunting M, Franklin MR, Thomas KR, Levy JE, et al. A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci USA. 2001;98(1):259-64.
81. Wang H, Long Q, Marty SD, Sassa S, Lin S. A zebrafish model for hepatoerythropoietic porphyria. Nat Genet. 1998;20(3):239-43.
82. Mori M, Gotoh S, Taketani S, Hiai H, Higuchi K. Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic mutation in the coproporphyrinogen oxidase gene. Exp Eye Res. 2013;112:45-50.
83. Ducamp S, Kannengiesser C, Touati M, Garcon L, Guerci-Bresler A, Guichard JF, et al. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Hum Mutat. 2011;32(6):590-7.
84. Bergmann AK, Campagna DR, McLoughlin EM, Agarwal S, Fleming MD, Bottomley SS, et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010;54(2):273-8.
85. Cotter PD, Baumann M, Bishop DF. Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency. Proc Natl Acad Sci USA. 1992;89(9):4028-32.
86. Camaschella C. Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. Semin Hematol. 2009;46(4):371-7.
87. Kannengiesser C, Sanchez M, Sweeney M, Hetet G, Kerr B, Moran E, et al. Missense SLC25A38 variations play an important role in autosomal recessive inherited sideroblastic anemia. Haematologica. 2011;96(6):808-13.
88. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum Mol Genet. 1999;8(5):743-9.
89. Lill R, Muhlenhoff U. Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms. Annu Rev Cell Dev Biol. 2006;22:457-86.
90. Camaschella C, Campanella A, De Falco L, Boschetto L, Merlini R, Silvestri L, et al. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood. 2007;110(4):1353-8.
91. Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, et al. Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest. 2010;120(5):1749-61.
92. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120(23):4496-504.
93. Sassa S, Kappas A. Molecular aspects of the inherited porphyrias. J Intern Med. 2000;247 (2):169-78.
94. Gouya L, Puy H, Robreau AM, Bourgeois M, Lamoril J, Da Silva V, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. 2002;30(1):27-8.
95. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. 2009;4:19.
96. Holme SA, Worwood M, Anstey AV, Elder GH, Badminton MN. Erythropoiesis and iron metabolism in dominant erythropoietic protoporphyria. Blood. 2007;110(12):4108-10.
97. Rademakers LH, Koningsberger JC, Sorber CW, Baart de la Faille H, Van Hattum J, Marx JJ. Accumulation of iron in erythroblasts of patients with erythropoietic protoporphyria. Eur J Clin Invest. 1993;23(2):130-8.
98. Whatley SD, Ducamp S, Gouya L, Grandchamp B, Beaumont C, Badminton MN, 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. Am J Hum Genet. 2008;83(3):408-14.
99. Schmitt C, Gouya L, Malonova E, Lamoril J, Camadro JM, Flamme M, et al. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria. Hum Mol Genet. 2005;14(20):3089-98.