2018 ABSTRACT BOOK EUROPEAN IRON CLUB ANNUAL MEETING 2018, ZÜRICH ORAL SESSIONS AND POSTERS ETH ZÜRICH | Rämistrasse 101, 8092 Zürich S ORAL SESSION ABSTRACTS Oral abstracts Feb 8 – Session 1 Biogenesis of iron-sulfur proteins in eukaryotes: An overview on components, mechanisms, and diseases Roland Lill, PhD Institut für Zytobiologie, Philipps-Universität Marburg – Germany E-mail: [email protected] Iron-sulfur (Fe/S) clusters are evolutionary ancient, inorganic cofactors of proteins with essential functions in catalysis, electron transfer and regulation. Synthesis of Fe/S clusters and their assembly into apoproteins in a living cell is a complex process involving more than 30 proteins in mitochondria and cytosol of eukaryotes (1- 4). Biogenesis of mitochondrial Fe/S proteins is accomplished by the iron-sulfur cluster (ISC) assembly machinery which was inherited from bacteria during evolution. Cytosolic and nuclear Fe/S protein assembly also depends on the function of this machinery, yet additionally requires the mitochondrial export apparatus and the cytosolic iron-sulfur protein assembly (CIA) machinery. While we have a good picture of the general outline of Fe/S protein biogenesis (Figure), the detailed molecular mechanisms underlying the individual reaction steps are only now being unraveled by biochemical, biophysical, bioinorganic and ultra-structural methods. The presentation will summarize new aspects concerning the basic mechanisms of cellular Fe/S protein maturation in yeast and human cells. I will also explain how functional impairment of the ISC components results in various “Fe/S diseases” with complex hematological, metabolic or neurodegenerative phenotypes [5]. References (Reviews) [1] Lill, R. (2009) Nature 460, 831-838. [2] Lill, R. et al. (2012) BBA 1823, 1491-1508; Braymer & Lill (2017) J. Biol. Chem. 292, 12754–63. [3] Netz, D.J., Mascarenhas, J., Stehling, O., Pierik, A.J., Lill, R. (2014) Trends Cell Biol 24, 303-312. [4] Paul, V.D. and Lill, R. (2015). BBA 1853, 1528-1539; and Cell Metab. 20, 384. [5] Stehling, O., Wilbrecht, C., & Lill, R. (2014). Biochimie 100, 61-77; and Stehling, O. & Lill, R. (2013). Cold Spring Harb Perspect Biol 5:a011312 1 Oral abstracts Feb 8 – Session 1 Systemic and cellular iron metabolism Martina U. Muckenthaler Department of Pediatrics, University of Heidelberg, Molecular Medicine Partnership Unit (EMBL), Heidelberg, Germany Imbalances of iron homeostasis account for some of the most common human diseases, whereby severe pathologies result from both iron deficiency and overload. At the cellular level iron homeostasis is maintained by the iron regulatory proteins (IRPs)-1 and -2 that posttranscriptionally control expression of proteins involved in iron uptake, storage and export. Interestingly, the IRE/IRP regulon extends beyond validated iron-related targets, suggesting links between iron metabolism and other physiological cellular processes. At the systemic level iron homeostasis is controlled by the hepcidin/ferroportin regulatory system. The small peptide hormone hepcidin orchestrates systemic iron fluxes and controls plasma iron levels by binding to the iron exporter ferroportin on the surface of iron releasing cell types, triggering its degradation and hence reducing iron transfer to transferrin. Hepcidin thus maintains transferrin saturation at physiological levels assuring adequate iron supplies to all cell types. My presentation will focus on regulatory mechanisms involved in maintaining iron homeostasis and the pathological consequences that arise if these systems are disrupted. 2 Oral abstracts Feb 8 – Session 1 The pioneering role of the Rennes school in haemochromatosis Pierre Brissot University of Rennes1 and Inserm-U 1241, Rennes, France This presentation is dedicated to the memory of Profs Michel Bourel and Marcel Simon who were the true Rennes pioneers in haemochromatosis (HC), to all colleagues and friends who got involved in this exciting adventure, and to all patients affected by this severe and still underdiagnosed disease. The Rennes studies have, over time, covered seven main domains: i) Contribution to the semiological description of HC. It concerned several aspects (dermatology, hepatology, endocrinology, rheumatology, and cardiology) ; ii) Refining new ways of investigating iron overload, among which ferritinemia, liver histology, liver iron concentration, and magnetic resonance imaging ; iii) Providing the first demonstration of the hereditary nature of the disease, based on the HLA approach ; iv) Emphasizing the importance of non-transferrin bound iron for explaining both cellular iron deposition and toxicity ; v) Demonstrating, for the first time, the role of hepcidin in iron metabolism ; vi) Refining the knowledge of non-HFE HC through the creation of the national reference center for rare genetic iron overload diseases ; vii) Giving patients their voice, via the creation of support structures at the regional, national (FFAMH, AHF), european (EFAPH) and global (HI) levels. 3 Oral abstracts Feb 8 – Session 1 Diagnosis of atypical iron overload disorders by next generation sequencing Domenico Girelli, MD PhD Department of Medicine, University of Verona Veneto Region Referral Center for Iron Metabolism Disorders, Policlinico G.B. Rossi, 37134 Verona Italy Atypical iron overload disorders (AIOD) are a heterogeneous group including a number of rare genetic diseases ranging from non-classical (or “non-HFE”) hereditary hemochromatosis (HH) to conditions in which iron accumulates at unusual sites, for example in the central nervous system. An accurate molecular diagnosis of these conditions has long been proven challenging. Traditionally, it required cumbersome and stepwise sequencing of candidate genes, prioritizing them on the basis of clinical clues (age of onset, ethnicity, phenotypic features fitting with current knowledge on HH subtypes). The advent of next-generation-sequencing (NGS) techniques is rapidly changing the scenario. Several Referral Centers are now able to perform targeted NGS allowing rapid and simultaneous analysis of gene panels, if not whole exome sequencing (WES) or whole genome sequencing (WGS). Costs are rapidly declining, potentially allowing an even more widespread use. Targeted NGS has been proven useful for the molecular diagnosis of many, but not all, cases with a provisional diagnosis of non-HFE HH after first level genetic testing (i.e. searching for the classical C282Y/H63D variants on the HFE gene). Among the interesting findings, digenic inheritance, i.e. compound heterozygosity for mutations in different genes proven to be causal, appears to occur not infrequently. Similarly, the substantial fraction of cases that remain unexplained after deep sequencing of the known five HH genes suggests that novel HH gene(s) have yet to be discovered. WES represents an attractive option for undiagnosed case. However, the long route from rough data produced by the sequencer to a plausible clinical diagnosis is challenging, and requires a close and constant collaboration between bioinformaticians and expert clinicians. Moreover, collaboration among Referral Centers, as well as the development of disease registries are both instrumental for proper advance in knowledge. 4 Oral abstracts Feb 8 – Session 2 How to define the need of iron supplementation in anaemia of inflammation and chronic kidney disease Prof. Igor Theurl University Hospital, Innsbruck Anaemia of chronic disease resulting from, for example, chronic kidney disease, cancer or autoimmune disease is the second most prevalent form of anaemia after iron deficiency anaemia and becomes even the most prevalent form within an in-patient setting. Despite its high prevalence and its significant impact on patient health and wellbeing, anaemia of chronic disease is often misdiagnosed and therefore poorly treated. This form of anaemia is driven by multiple factors including EPO deficiency and resistance, a direct negative effect on red blood cell precursors, reduced red blood cell survival and the reduced availability of iron due to misdistribution within the body. Anaemia of chronic disease is not driven by iron deficiency, but by a reduced availability of functional iron in the blood. Routine laboratory tests are usually only designed to detect iron deficiency, making the diagnosis of anaemia of chronic disease challenging. However, in most cases, the correct diagnosis of this form can be achieved quickly and at relatively low cost. This requires a better understanding of options and limitations of the iron and erythropoiesis tests available to the physician, coupled with a deeper understanding of the known pathology of the underlying disease. Each form of anaemia has a different set of treatment options and since there is a growing number of novel and expensive treatments, it is critical to determine the correct diagnosis to prescribe the best treatment. To benefit patients and to reduce overall healthcare costs, it is essential to establish standardised laboratory indicators and decision trees to guide diagnosis and optimal treatment. 5 Oral abstracts Feb 8 – Session 2 Intravenous iron for non-anemic patients – the heart failure clinical story 2000-2018. Professor Stefan D Anker, MD PhD Division of Cardiology and Metabolism; Department of Cardiology (CVK); Berlin-Brandenburg Center for Regenerative Therapies (BCRT); Charité Universitätsmedizin Berlin, Germany. [email protected] Iron is importantly involved in numerous physiological processes including oxygen transport