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Ferrata Storti Foundation
Iron Metabolism & its Disorders
The SLC40A1 R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism
Chandran Ka,1,2,3* Julie Guellec,1,3,4* Xavier Pepermans,5 Caroline Kannengiesser,3,6,7 Cécile Ged,7,8 Wim Wuyts,9 David Cassiman,10
Victor de Ledinghen,11 Bruno Varet,12 Caroline de Kerguenec,13 Claire Oudin,6 Isabelle Gourlaouen,1,3 Thibaud Lefebvre,6 Claude Férec,1,2,7
Isabelle Callebaut14 and Gérald Le Gac1,2,3,7
Haematologica 2018 Volume 103(11):1796-1805
1UMR1078, INSERM, Université Bretagne Loire – Université de Bretagne Occidentale, Etablissement Français du Sang – Bretagne, Institut Brestois Santé-Agro-Matière, Brest, France; 2Laboratoire de Génétique Moléculaire et Histocompatibilité, CHRU de Brest, Hôpital Morvan, France; 3Laboratory of Excellence GR-Ex, Paris, France; 4Association Gaetan Saleun, Brest, France; 5Center for Human Genetics, University Hospital of St- Luc, Brussels, Belgium; 6UMR1149, INSERM, Centre de Recherche sur l'Inflammation, Université Paris Diderot, AP-HP, Hôpital Bichat, Département de Génétique, France; 7On behalf of the French National Network for the Molecular Diagnosis of Inherited Iron Overload Disorders (J. Rochette, E. Cadet, C. Kannengiesser, H. Puy, C. Ged, H. de Verneuil, G. Le Gac, C. Férec, S. Pissard, V. Gérolami), Brest, France; 8INSERM U1035, BMGIC, CHU de Bordeaux, Laboratoire de Biochimie et Biologie Moléculaire, France; 9Department of Medical Genetics, University and University Hospital of Antwerp, Edegem, Belgium; 10Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital of Leuven, Belgium; 11Department of Gastroenterology and Digestive Oncology, University Hospital of Bordeaux, France; 12Université Paris Descartes et AP-HP, Hôpital Necker, Service d’Hématologie, France; 13AP-HP, Hôpital Beaujon, Département d'Hépatologie, Clichy, France and 14UMR7590, CNRS, Sorbonne Universités, Université Pierre et Marie Curie-Paris, France
*CK and JG contributed equally to this work
ABSTRACT
Hemochromatosis type 4 is one of the most common causes of pri- mary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense muta- tions in SLC40A1. This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous mis- sense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperfer- ritinemia. Structure/function analysis is the most effective way of estab- lishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We pres- ent the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevat- ed serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mis- localization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformation- al changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of “gating residues” is necessary in order to fully understand the action mechanism of FPN1.
Correspondence:
gerald.legac@univ-brest.fr
Received: January 29, 2018. Accepted: July 6, 2018. Pre-published: July 12, 2018.
doi:10.3324/haematol.2018.189845
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1796
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