DOCSLIB.ORG

Leaders Molecular Genetics of Disorders of Haem Biosynthesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Leaders Molecular Genetics of Disorders of Haem Biosynthesis J. Clin Pathol 1993;46:977-981 977 ;; Leaders :;:::::;::;::;::;::;::;::;::;: ;:; ;;;;;;;;;;:;; J Clin Pathol: first published as 10.1136/jcp.46.11.977 on 1 November 1993. Downloaded from Molecular genetics of disorders of haem biosynthesis G H Elder Introduction chelatase,20 and ,B globin genes,2' contains Haem is synthesised in all animal cells from sequences that interact with the trans-acting succinyl CoA and glycine by a sequence of erythroid specific factors, GATA-1 and NF- reactions catalysed by eight enzymes.1 E2, and regulate transcription during ery- Absence of any one of these enzymes is throid differentiation.5 The 5' untranslated incompatible with life because haem is an region (UTR) of ALAS2 mRNA, unlike essential component of respiratory proteins. ALAS 1 mRNA, contains a sequence struc- Partial deficiencies occur, however, and cause ture motif that closely resembles the iron disease (table 1).12 The activity of 5-amino- responsive elements (IREs) found in the 5' laevulinate (ALA) synthase, the first and rate UTR of ferritin mRNA and the 3' UTR of controlling enzyme of the pathway, is transferrin receptor mRNA.i22 Iron deficiency decreased in the bone marrow in hereditary leads to high affinity binding of an IRE-bind- sideroblastic anaemias,3 while deficiency of ing protein to these elements with consequent each of the subsequent enzymes produces a inhibition of translation of ALAS2 and fer- particular type of porphyria (table 1) .1 2 The ritin mRNAs and stabilisation of transferrin enzyme defect in each porphyria is inherited receptor mRNA,22 a mechanism that allows (table 1), except in type I porphyria cutanea co-ordination of protoporphyrin formation tarda which appears to be an acquired dis- with iron supply. The presequences of both order. The clinical features and laboratory ALAS isoenzymes also contain a conserved, diagnosis of the porphyrias have been haem regulatory motif which is involved in reviewed.' 2 inhibition by haem of their transport into Genes or cDNAs have now been isolated mitochondria.424 and characterised for all but two of the The discovery that ALAS2 maps to the X human enzymes (table 2). These advances chromosome prompted a search for muta- have been followed rapidly by identification tions in this gene in sideroblastic anaemia. A of mutations in the corresponding diseases T-÷A transition that converts isoleucine to and by the application of DNA techniques to asparagine has recently been identified in a http://jcp.bmj.com/ the management of families with these condi- man with severe, pyridoxine responsive tions. This review summarises current infor- sideroblastic anaemia.25 This mutation is in a mation about the molecular genetics of each highly conserved region of exon 9 that is close disorder. to the putative pyridoxal phosphate binding lysine residue and thus may impair binding of Hereditary sideroblastic anaemias the cofactor. This man had no family history The hereditary sideroblastic anaemias are a of anaemia but a second mutation in the on September 27, 2021 by guest. Protected copyright. mixed group of disorders in which the most ALAS2 gene has now been found in a family frequent pattern of inheritance indicates link- with X linked pyridoxine responsive sidero- age to the X chromosome. Bone marrow blastic anaemia.26 Because the low level of ALA synthase activity is usually decreased.' expression of ALAS 1 in erythroid cells is Pyridoxal phosphate is an essential cofactor unlikely to be sufficient by itself for erythro- for this enzyme and patients may respond to poiesis,5 other inherited ALAS2 defects in treatment with pyridoxine.3 sideroblastic anaemia are similarly likely to Mammals have two ALA synthase genes result from point mutations that modify but (table 2). The X chromosome gene encodes do not abolish enzyme activity. Not all ALAS2 which is expressed only in erythroid families with X linked sideroblastic anaemia cells while that on chromosome 3 encodes a have defects in the ALAS2 gene. Combined housekeeping isoenzyme (ALAS 1) that is use of a highly polymorphic dinucleotide found in all tissues.F6 The C-terminal portion repeat in intron 7 of the gene and other X of ALAS2 (exons 5-11) has 73% sequence chromosome polymorphic markers in linkage identity with ALAS1 and contains the cata- studies has shown that there are at least two lytic domain. Exons 2-4 of the ALAS2 gene X loci for sideroblastic anaemia.26 Overall, encode the N-terminal signal sequence that these studies suggest that analysis of the Departent of directs mitochondrial import and an inter- ALAS2 gene is likely to improve both diagno- Medical vening section that undergoes differential sis and classification of these anaemias and Biochemistry, University of Wales pre-mRNA splicing to generate two isoforms may even reveal a role for somatic mutation College of Medicine, (table 2).6 The functional importance of this of this gene in some acquired forms. Cardiff CF4 4XN pattern of processing has not been estab- G H Elder lished.6 Expression of the ALAS2 gene is Autosomal dominant porphyrias Correspondence to: Professor G H Elder regulated at transcriptional and translational The enzyme defects in most porphyrias are Accepted for publication levels. Its promoter region, in common with inherited in an autosomal dominant manner 17 March 1993 those of the erythroid PBGD,2' ferro- (table 1). The clinical penetrance of these 978 Elder Table 1 Disorders caused by partial deficiencies ofhaem biosynthetic enzymes exclude exon 2. Translation then proceeds Disorder Enzyme deficiency Inhenitance from a start codon in exon 1 so that the housekeeping isoenzyme is 17 amino acids J Clin Pathol: first published as 10.1136/jcp.46.11.977 on 1 November 1993. Downloaded from 1 Sideroblastic anaemia ALA synthase (AIAS2) X-linked 2 PBG deficiency porphyria PBG synthase (PBGS) AR longer at the N-terminus than the erythroid 3 Acute intermittent porphyria PBG deaminase (PBGD) AD form. Mutations that affect both isoenzymes 4 Congenital erythropoietic porphyria Uroporphyrinogen synthase (UROS) AR 5 Porphyria cutanea tarda Uroporphyrinogen decarboxylase (UROD) see text would thus be predicted to occur in exons 6 Hereditary coproporphyria Coproporphyrinogen oxidase (COPROX) AD 3-15 or in intronic sequences that determine 7 Variegate porphyria Protoporphyrinogen oxidase (PROTOX) AD 8 Erythropoietic protoporphyria Ferrochelatase (FC) AD the structure or level of expression of the corresponding mRNA. AR: AD: autosomal recessive; autosomal dominant; PBG: porphobilinogen. Three subtypes of AIP can be distin- guished by measurement of erythrocyte PBGD: an uncommon (less than 5% of disorders, however, is low; in each condition families) form in which erythrocyte PBGD is more than 80% of those who inherit the normal with only the ubiquitous isoenzyme genetic defect never have symptoms and most being defective; a form in which the product of these have no detectable biochemical of the mutant allele cross-reacts immuno- abnormality apart from enzyme deficiency. logically with antiserum to normal enzyme The frequency of the genes for these condi- but has absent or substantially impaired cata- tions in the population is sufficiently high for lytic activity (CRIM positive); and CRIM homozygous forms of each disorder to occur negative AIP in which immunoreactivity and without consanguinity127 and for occasional catalytic activity are decreased in parallel. co-inheritance of two separate porphyrias.28 Mutations have been identified in all three subtypes. In the non-erythroid subtype two ACUTE INTERM=ITENT PORPHYRIA mutations that affect the splicing of exon 1 Acute intermittent porphyria (AIP) is the during pre-mRNA processing and thus commonest of the acute hepatic porphyrias impair the formation of mRNA for the ubiq- and at present is the only one that has been uitous isoenzyme only have been found in investigated at the DNA level. It is charac- seven of 10 unrelated patients.29 About 15% terised by life-threatening acute neurovisceral of unrelated patients with AIP have the attacks that are frequently precipitated by CRIM positive subtype. Studies from the drugs, calorie restriction, or alcohol.' Detec- Netherlands and France suggest that about tion of asymptomatic gene carriers so that 75% of these patients have mutations that they can be advised to avoid known lead to replacement of either of two con- precipitants of acute attacks is an important served arginine residues (R167 and R173) in part of the management of AIP families.' 2 exon 10 by glutamine or tryptophan with one AIP is caused by porphobilinogen deami- mutation (G-+A at base position 500; nase (PBGD) deficiency. Enzyme activity is R1 67Q) being more frequent than the close to 50% of normal, reflecting expression others.3031 These mutations severely impair of the normal gene allelic to the mutant gene. but do not abolish enzyme activity.32 Inter- http://jcp.bmj.com/ As with ALA synthase, there are separate estingly, the only two unrelated cases of erythroid and housekeeping isoenzymes of homozygous AIP that have been reported PBG deaminase (table 2)9; current evidence were both compound heterozygotes for three suggests that there are no tissue specific of the CRIM positive exon 10 mutations,3 isoenzymes for the other enzymes of the suggesting that their frequency may be higher pathway. In contrast to ALA synthase, how- than the prevalence of overt CRIM positive ever, PBGD is encoded by a single gene AIP would indicate. The structure of PBG on September 27, 2021 by guest. Protected copyright. (table 2) which is transcribed from separate deaminase is highly conserved with over 45% erythroid specific and housekeeping pro- amino acid sequence identity between the moters.910 The erythroid promoter lies in Escherichia coli and human enzymes. X-ray intron 1 and transcription is initiated 5' to analysis of the crystal structure of the E coli exon 2. Translation of erythroid mRNA starts enzyme shows that the arginine residues cor- in exon 3 so that the erythroid isoenzyme responding to these two residues in exon 10 contains sequence encoded by exons 4-15 of human PBGD and a third one in exon 3, and a 3' section of exon 3.
Load more

Recommended publications
  • Molecular Expression, Characterization and Mechanism of ALAS2 Gain-Of-Function Mutants Vassili Tchaikovskii, Robert J
    Tchaikovskii et al. Molecular Medicine (2019) 25:4 Molecular Medicine https://doi.org/10.1186/s10020-019-0070-9 RESEARCHARTICLE Open Access Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants Vassili Tchaikovskii, Robert J. Desnick and David F. Bishop* Abstract Background: X-linked protoporphyria (XLP) (MIM 300752) is an erythropoietic porphyria due to gain-of-function mutations in the last exon (Ducamp et al., Hum Mol Genet 22:1280-88, 2013) of the erythroid-specific aminolevulinate synthase gene (ALAS2). Five ALAS2 exon 11 variants identified by the NHBLI Exome sequencing project (p.R559H, p.E565D, p.R572C, p.S573F and p.Y586F) were expressed, purified and characterized in order to assess their possible contribution to XLP. To further characterize the XLP gain-of-function region, five novel ALAS2 truncation mutations (p.P561X, p.V562X, p.H563X, p.E569X and p.F575X) were also expressed and studied. Methods: Site-directed mutagenesis was used to generate ALAS2 mutant clones and all were prokaryotically expressed, purified to near homogeneity and characterized by protein and enzyme kinetic assays. Standard deviations were calculated for 3 or more assay replicates. Results: The five ALAS2 single nucleotide variants had from 1.3- to 1.9-fold increases in succinyl-CoA Vmax and 2- to 3-fold increases in thermostability suggesting that most could be gain-of-function modifiers of porphyria instead of causes. One SNP (p.R559H) had markedly low purification yield indicating enzyme instability as the likely cause for XLSA in an elderly patient with x-linked sideroblastic anemia. The five novel ALAS2 truncation mutations had increased Vmax values for both succinyl-CoA and glycine substrates (1.4 to 5.6-fold over wild-type), while the Kms for both substrates were only modestly changed.
    [Show full text]
  • GATA Transcription Factors Directly Regulate the Parkinson's
    GATA transcription factors directly regulate the Parkinson’s disease-linked gene ␣-synuclein Clemens R. Scherzer*†‡, Jeffrey A. Grass§, Zhixiang Liao*, Imelda Pepivani*, Bin Zheng*, Aron C. Eklund*, Paul A. Ney¶, Juliana Ngʈ, Meghan McGoldrick*, Brit Mollenhauer*, Emery H. Bresnick†§**, and Michael G. Schlossmacher*†ʈ†† *Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Cambridge, MA 02139; §Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706; ¶Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN 38105; and ʈDivision of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada K1H 8M5 Edited by Gregory A. Petsko, Brandeis University, Waltham, MA, and approved May 27, 2008 (received for review March 13, 2008) Increased ␣-synuclein gene (SNCA) dosage due to locus multipli- Results cation causes autosomal dominant Parkinson’s disease (PD). Vari- SNCA mRNA and Protein Are Highly Abundant in Human and Mouse ation in SNCA expression may be critical in common, genetically Erythroid Cells. Relative SNCA mRNA abundance was determined complex PD but the underlying regulatory mechanism is unknown. by comparing the SNCA mRNA abundance in each target tissue to We show that SNCA and the heme metabolism genes ALAS2, FECH, the calibrator Universal Human Reference RNA (Fig. 1A). SNCA and BLVRB form a block of tightly correlated gene expression in 113 mRNA abundance was high in whole blood from human donors samples of human blood, where SNCA naturally abounds (vali- (relative abundance 10 {range 6.6–15.3}) with very high levels in ؊ ؊ ؊ -؋ 10 11, 1.8 ؋ 10 10, and 6.6 ؋ 10 5).
    [Show full text]
  • Case Reports
    CASE REPORTS The 5’ untranslated region (UTR) of ALAS2 mRNA A mutation in the iron-responsive element of contains a cis-regulatory iron-responsive element (IRE) ALAS2 is a modifier of disease severity in a that confers iron-dependent posttranscriptional regula - patient suffering from CLPX associated erythro - tion by the iron regulatory proteins (IRP). 7 IRE muta - poietic protoporphyria tions are known to cause human diseases. IRE muta - tions in ferritin L mRNA cause hereditary hyperferritine - Porphyrias are a group of eight genetically distinct dis - mia with cataract syndrome (HHCS) (OMIM orders, each resulting from a partial deficiency or gain-of- #600886), 8-9 and a single point mutation in the IRE of function of a specific enzyme in the heme biosynthetic ferritin H is responsible for an autosomal dominant iron 1 pathway. Porphyrias are inherited as autosomal domi - overload phenotype (OMIM #615517). 10 These cases 2 nant, autosomal recessive or X-linked traits. suggest a possible role for IRE mutations in the ALAS2 Erythropoietic protoporphyria (EPP) is a constitutive gene in modifying the severity of hematologic diseases. hematological disorder characterized by protoporphyrin Here, we describe an 18 year-old Caucasian female IX (PPIX) accumulation in erythrocytes and other tissues proband (III:2, Figure 1A) referred to the French Center resulting in acute skin photosensitivity, mild microcytic of Porphyria because of early onset (9 months) acute anemia, and rarely, severe liver disease. The majority of photosensitivity characterized by painfully phototoxic the patients with EPP present the autosomal EPP form reactions suggesting EPP. An incomplete genetic charac - (OMIM #177000) due to a partial deficiency of fer - terization of this case was previously reported to harbor rochelatase (FECH), the last enzyme of the heme biosyn - a gain of function in the mitochondrial unfoldase gene, thetic pathway.
    [Show full text]
  • REPORT C-Terminal Deletions in the ALAS2 Gene Lead to Gain of Function and Cause X-Linked Dominant Protoporphyria Without Anemia Or Iron Overload
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REPORT C-Terminal Deletions in the ALAS2 Gene Lead to Gain of Function and Cause X-linked Dominant Protoporphyria without Anemia or Iron Overload Sharon D. Whatley,1,9 Sarah Ducamp,2,3,9 Laurent Gouya,2,3 Bernard Grandchamp,3,4 Carole Beaumont,3 Michael N. Badminton,1 George H. Elder,1 S. Alexander Holme,5 Alexander V. Anstey,5 Michelle Parker,6 Anne V. Corrigall,6 Peter N. Meissner,6 Richard J. Hift,6 Joanne T. Marsden,7 Yun Ma,8 Giorgina Mieli-Vergani,8 Jean-Charles Deybach,2,3,* and Herve´ Puy2,3 All reported mutations in ALAS2, which encodes the rate-regulating enzyme of erythroid heme biosynthesis, cause X-linked sideroblastic anemia. We describe eight families with ALAS2 deletions, either c.1706-1709 delAGTG (p.E569GfsX24) or c.1699-1700 delAT (p.M567EfsX2), resulting in frameshifts that lead to replacement or deletion of the 19–20 C-terminal residues of the enzyme. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. These gain-of-function mutations cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-proto- porphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease. Each of the seven inherited porphyrias results from a partial mutations in about 7% of EPP families, of which about deficiency of an enzyme of heme biosynthesis.
    [Show full text]
  • Loss-Of-Function Ferrochelatase and Gain-Of-Function Erythroid-Specific
    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 Manisha Balwani,1* Dana Doheny,1* David F Bishop,1* Irina Nazarenko,1 Makiko Yasuda,1 Harry A Dailey,2 Karl E Anderson,3 D Montgomery Bissell,4 Joseph Bloomer,5 Herbert L Bonkovsky,6 John D Phillips,7 Lawrence Liu,8 and Robert J Desnick,1 on behalf of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America; 2Department of Microbiology and Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, United States of America; 3Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas, United States of America; 4Department of Medicine, University of California, San Francisco, California, United States of America; 5Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America; 6Department of Medicine, Carolinas Medical Center and HealthCare System, Charlotte, North Carolina, United States of America; 7Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States of America; 8Department of Medicine, Mount Sinai School of Medicine, New York, New York, United States of America Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phe- notype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH ) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively.
    [Show full text]
  • Mir-218 Inhibits Erythroid Differentiation and Alters Iron Metabolism by Targeting ALAS2 in K562 Cells
    Article miR-218 Inhibits Erythroid Differentiation and Alters Iron Metabolism by Targeting ALAS2 in K562 Cells Yanming Li 1,2,†, Shuge Liu 1,2,†, Hongying Sun 1,†, Yadong Yang 1, Heyuan Qi 1,2, Nan Ding 1,2, Jiawen Zheng 1,2, Xunong Dong 1,2, Hongzhu Qu 1, Zhaojun Zhang 1 and Xiangdong Fang 1,* Received: 9 October 2015; Accepted: 17 November 2015; Published: 26 November 2015 Academic Editor: Martin Pichler 1 CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; [email protected] (Y.L.); [email protected] (S.L.); [email protected] (H.S.); [email protected] (Y.Y.); [email protected] (H.Q.); [email protected] (N.D.); [email protected] (J.Z.); [email protected] (X.D.); [email protected] (H.Q.); [email protected] (Z.Z.) 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China * Correspondence: [email protected]; Tel.: +86-10-8409-7495; Fax: +86-10-8409-7720 † These authors contributed equally to this work. Abstract: microRNAs (miRNAs) are involved in a variety of biological processes. The regulatory function and potential role of miRNAs targeting the mRNA of the 51-aminolevulinate synthase 2 (ALAS2) in erythropoiesis were investigated in order to identify miRNAs which play a role in erythroid iron metabolism and differentiation. Firstly, the role of ALAS2 in erythroid differentiation and iron metabolism in human erythroid leukemia cells (K562) was confirmed by ALAS2 knockdown. Through a series of screening strategies and experimental validations, it was identified that hsa-miR-218 (miR-218) targets and represses the expression of ALAS2 by binding to the 31-untranslated region (UTR).
    [Show full text]
  • Significance of Heme and Heme Degradation in the Pathogenesis Of
    International Journal of Molecular Sciences Review Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders Stefan W. Ryter Proterris, Inc., Boston, MA 02118, USA; [email protected] Abstract: The heme molecule serves as an essential prosthetic group for oxygen transport and storage proteins, as well for cellular metabolic enzyme activities, including those involved in mitochondrial respiration, xenobiotic metabolism, and antioxidant responses. Dysfunction in both heme synthesis and degradation pathways can promote human disease. Heme is a pro-oxidant via iron catalysis that can induce cytotoxicity and injury to the vascular endothelium. Additionally, heme can modulate inflammatory and immune system functions. Thus, the synthesis, utilization and turnover of heme are by necessity tightly regulated. The microsomal heme oxygenase (HO) system degrades heme to carbon monoxide (CO), iron, and biliverdin-IXα, that latter which is converted to bilirubin-IXα by biliverdin reductase. Heme degradation by heme oxygenase-1 (HO-1) is linked to cytoprotection via heme removal, as well as by activity-dependent end-product generation (i.e., bile pigments and CO), and other potential mechanisms. Therapeutic strategies targeting the heme/HO-1 pathway, including therapeutic modulation of heme levels, elevation (or inhibition) of HO-1 protein and activity, and application of CO donor compounds or gas show potential in inflammatory conditions including sepsis and pulmonary diseases. Keywords: acute lung injury; carbon monoxide; heme; heme oxygenase; inflammation; lung dis- ease; sepsis Citation: Ryter, S.W. Significance of Heme and Heme Degradation in the Pathogenesis of Acute Lung and Inflammatory Disorders. Int. J. Mol. 1. Introduction Sci.
    [Show full text]
  • Coordinate Expression of Heme and Globin Is Essential for Effective Erythropoiesis
    Coordinate expression of heme and globin is essential for effective erythropoiesis Raymond T. Doty, … , Siobán B. Keel, Janis L. Abkowitz J Clin Invest. 2015;125(12):4681-4691. https://doi.org/10.1172/JCI83054. Research Article Hematology Erythropoiesis requires rapid and extensive hemoglobin production. Heme activates globin transcription and translation; therefore, heme synthesis must precede globin synthesis. As free heme is a potent inducer of oxidative damage, its levels within cellular compartments require stringent regulation. Mice lacking the heme exporter FLVCR1 have a severe macrocytic anemia; however, the mechanisms that underlie erythropoiesis dysfunction in these animals are unclear. Here, we determined that erythropoiesis failure occurs in these animals at the CFU-E/proerythroblast stage, a point at which the transferrin receptor (CD71) is upregulated, iron is imported, and heme is synthesized — before ample globin is produced. From the CFU-E/proerythroblast (CD71+ Ter119– cells) stage onward, erythroid progenitors exhibited excess heme content, increased cytoplasmic ROS, and increased apoptosis. Reducing heme synthesis in FLVCR1-defient animals via genetic and biochemical approaches improved the anemia, implying that heme excess causes, and is not just associated with, the erythroid marrow failure. Expression of the cell surface FLVCR1 isoform, but not the mitochondrial FLVCR1 isoform, restored normal rbc production, demonstrating that cellular heme export is essential. Together, these studies provide insight into how heme is regulated to allow effective erythropoiesis, show that erythropoiesis fails when heme is excessive, and emphasize the importance of evaluating Ter119– erythroid cells when studying erythroid marrow failure in murine models. Find the latest version: https://jci.me/83054/pdf The Journal of Clinical Investigation RESEARCH ARTICLE Coordinate expression of heme and globin is essential for effective erythropoiesis Raymond T.
    [Show full text]
  • Acute Intermittent Porphyria: an Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators
    International Journal of Molecular Sciences Review Acute Intermittent Porphyria: An Overview of Therapy Developments and Future Perspectives Focusing on Stabilisation of HMBS and Proteostasis Regulators Helene J. Bustad 1 , Juha P. Kallio 1 , Marta Vorland 2, Valeria Fiorentino 3 , Sverre Sandberg 2,4, Caroline Schmitt 3,5, Aasne K. Aarsand 2,4,* and Aurora Martinez 1,* 1 Department of Biomedicine, University of Bergen, 5020 Bergen, Norway; [email protected] (H.J.B.); [email protected] (J.P.K.) 2 Norwegian Porphyria Centre (NAPOS), Department for Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway; [email protected] (M.V.); [email protected] (S.S.) 3 INSERM U1149, Center for Research on Inflammation (CRI), Université de Paris, 75018 Paris, France; valeria.fi[email protected] (V.F.); [email protected] (C.S.) 4 Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, 5009 Bergen, Norway 5 Assistance Publique Hôpitaux de Paris (AP-HP), Centre Français des Porphyries, Hôpital Louis Mourier, 92700 Colombes, France * Correspondence: [email protected] (A.K.A.); [email protected] (A.M.) Abstract: Acute intermittent porphyria (AIP) is an autosomal dominant inherited disease with low clinical penetrance, caused by mutations in the hydroxymethylbilane synthase (HMBS) gene, which encodes the third enzyme in the haem biosynthesis pathway. In susceptible HMBS mutation carriers, triggering factors such as hormonal changes and commonly used drugs induce an overproduction Citation: Bustad, H.J.; Kallio, J.P.; and accumulation of toxic haem precursors in the liver. Clinically, this presents as acute attacks Vorland, M.; Fiorentino, V.; Sandberg, characterised by severe abdominal pain and a wide array of neurological and psychiatric symptoms, S.; Schmitt, C.; Aarsand, A.K.; and, in the long-term setting, the development of primary liver cancer, hypertension and kidney Martinez, A.
    [Show full text]
  • Zebrafish Models for Human ALA-Dehydratase-Deficient Porphyria (ADP) And
    bioRxiv preprint doi: https://doi.org/10.1101/109553; this version posted February 17, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Zebrafish models for human ALA-dehydratase-deficient porphyria (ADP) and 2 hereditary coproporphyria (HCP) generated with TALEN and CRISPR-Cas9 3 4 5 Shuqing Zhang1,2, Jiao Meng1,2, Zhijie Niu1,2, Yikai Huang2, Jingjing Wang1,2, Xiong 2 3 1,2* 6 Su , Yi Zhou , Han Wang 7 8 1Center for Circadian Clocks, Soochow University, Suzhou 215123, Jiangsu, China 9 2School of Biology & Basic Medical Sciences, Medical College, Soochow University, 10 Suzhou 215123, Jiangsu, China 3 Stem Cell Program and Division of Pediatric 11 Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, 12 Harvard Medical School, Boston, MA 02115, USA. 13 14 15 * To whom correspondence should be addressed at: Han Wang, Center for Circadian 16 Clocks, Soochow University, 199 Renai Road, Suzhou, Jiangsu 215123, China. Tel: 17 +86 51265882115; Fax: +86 51265882115; Email: [email protected] or 18 [email protected] 19 20 21 Running title: Zebrafish models for human porphyrias ADP and HCP 22 23 24 1 bioRxiv preprint doi: https://doi.org/10.1101/109553; this version posted February 17, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 ABSTRACT: Defects in the enzymes involved in heme biosynthesis result in a group 26 of human metabolic genetic disorders known as porphyrias.
    [Show full text]
  • ALAS2 Gene 5-Aminolevulinate Synthase 2
    ALAS2 gene 5'-aminolevulinate synthase 2 Normal Function The ALAS2 gene provides instructions for making an enzyme called 5'-aminolevulinate synthase 2 or erythroid ALA-synthase. This version of the enzyme is found only in developing red blood cells called erythroblasts. ALA-synthase plays an important role in the production of heme. Heme is a component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Heme is vital for all of the body's organs, although it is most abundant in the blood, bone marrow, and liver. The production of heme is a multi-step process that requires eight different enzymes. ALA-synthase is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (ALA). In subsequent steps, seven other enzymes produce and modify compounds that ultimately lead to heme. Health Conditions Related to Genetic Changes Porphyria At least two ALAS2 gene mutations have been found in people with a form of porphyria known as X-linked dominant erythropoietic protoporphyria. Each of these mutations deletes a small amount of genetic material near the end of the ALAS2 gene. These changes overactivate erythroid ALA-synthase, which increases the production of ALA within red blood cells. The excess ALA is converted by other enzymes to compounds called porphyrins. If these compounds build up in erythroblasts, they can leak out and be transported through the bloodstream to the skin and other tissues. High levels of porphyrins in the skin cause the oversensitivity to sunlight that is characteristic of this condition.
    [Show full text]
  • Circadian Rhythms in Acute Intermittent Porphyria a Pilot Study
    DOI: 10.1111/eci.12102 ORIGINAL ARTICLE Circadian rhythms in acute intermittent porphyria – a pilot study Sebastian Larion*, Frederick R. Caballes*,†, Sun-Il Hwang*,‡, Jin-Gyun Lee*,‡, Whitney E. Rossman*,‡, Judy Parsons‡, Nury Steuerwald*,‡, Ting Li*,‡, Vinaya Maddukuri*,†, Gale Groseclose*,‡, Carla V. Finkielstein§ and Herbert L. Bonkovsky*,‡ *The Liver-Biliary-Pancreatic Center, Carolinas HealthCare System, Charlotte, NC, USA, †Department of Medicine, Carolinas HealthCare System, Charlotte, NC, USA, ‡Department of Research, Carolinas HealthCare System, Charlotte, NC, USA, §The Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Tech University, Blacksburg, VA, USA ABSTRACT Background Acute intermittent porphyria (AIP) is an inherited disorder of haem synthesis wherein a partial deficiency of porphobilinogen (PBG) deaminase (PBGD) with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic haem deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid (ALA) synthase-1 (ALAS1) with over-production of ALA and PBG. The treatment of choice is intravenous haem, which restores the deficient regulatory haem pool of the liver and represses ALAS1. Recently, haem has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. Materials and methods Over a 21-h period, we measured levels of serum cortisol, melatonin, ALA, PBG and mRNA levels (in peripheral blood mononuclear cells) of selected clock-controlled genes and genes involved in haem synthesis in 10 Caucasian (European-American) women who were either postmenopausal or had been receiving female hormone therapy, six of whom have AIP and four do not and are considered controls.
    [Show full text]