• Kamel Laghmani, Bodo B Beck, Sung-Sen Yang, Elie Seaayfan, Andrea Wenzel, Björn Reusch, Helga Vitzthum, Dario Priem, Sylvie Demaretz, Klasien Bergmann, Leonie K Duin, Heike Göbel, Christoph Mache, Holger Thiele, Malte P Bartram, Carlos Dombret, Janine Altmüller, Peter Nürnberg, Thomas Benzing, Elena Levtchenko, Hannsjörg W Seyberth, Günter Klaus, Gökhan Yigit, Shih-Hua Lin, Albert Timmer, Tom J de Koning, Sicco A Scherjon, Karl P Schlingmann, Mathieu J M Bertrand, Markus M Rinschen, Olivier de Backer, Martin Konrad, and Martin Kömhoff.
• From INSERM, Centre de Recherche des Cordeliers, Unité 1138, Centre National de la Recherche Scientifique, ERL8228 Université Pierre et Marie Curie and Université Paris-Descartes, Paris (K.L., E.S., S.D.); Institute of Human Genetics (B.B.B., A.W., B.R., J.A., G.Y.), Department of Pathology (H.G.), Cologne Center for Genomics and Center for Molecular Medicine (H.T., J.A., P.N.), Department II of Internal Medicine and Center for Molecular Medicine Cologne (M.P.B., T.B., M.M.R.), and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases and Systems Biology of Aging Cologne (T.B., M.M.R.) - all at the University of Cologne, Cologne, the Department of Cellular and Integrative Physiology, University Medical Center Hamburg, Hamburg (H.V.), University Children's Hospital, Philipps University Marburg (H.W.S.), and Kuratorium für Heimdialyse, Pediatric Kidney Center (G.K.), Marburg, the Institute of Human Genetics, University Health Services Göttingen, Göttingen (G.Y.), and the Department of General Pediatrics, University Hospital Münster, Münster (K.P.S., M. Konrad) - all in Germany; the Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center (S.-S.Y., S.-H.L.), and Institute of BioMedical Sciences, Academia Sinica (S.-S.Y.) - both in Taipei, Taiwan; the Department of Biomedical Molecular Biology, Inflammation Research Center, VIB/Ghent University, Ghent (D.P., M.J.M.B.), Unité de Recherche en Physiologie Moléculaire, University of Namur, Namur (C.D., O.B.), and the Division of Nephrology, University Children's Hospital Leuven (E.L.) - all in Belgium; the Divisions of Neonatology (K.B.) and Nephrology (M. Kömhoff), Beatrix Children's Hospital, and the Departments of Obstetrics and Gynecology (L.K.D., S.A.S.), Pathology and Medical Biology (A.T.), and Genetics (T.J.K.) - all at University Medical Center Groningen, Groningen, the Netherlands; and University Children's Hospital Graz
• N. Engl. J. Med. 2016 May 12; 374 (19): 1853-63.

BackgroundThree pregnancies with male offspring in one family were complicated by severe polyhydramnios and prematurity. One fetus died; the other two had transient massive salt-wasting and polyuria reminiscent of antenatal Bartter's syndrome.MethodsTo uncover the molecular cause of this possibly X-linked disease, we performed whole-exome sequencing of DNA from two members of the index family and targeted gene analysis of other members of this family and of six additional families with affected male fetuses. We also evaluated a series of women with idiopathic polyhydramnios who were pregnant with male fetuses. We performed immunohistochemical analysis, knockdown and overexpression experiments, and protein-protein interaction studies.ResultsWe identified a mutation in MAGED2 in each of the 13 infants in our analysis who had transient antenatal Bartter's syndrome. MAGED2 encodes melanoma-associated antigen D2 (MAGE-D2) and maps to the X chromosome. We also identified two different MAGED2 mutations in two families with idiopathic polyhydramnios. Four patients died perinatally, and 11 survived. The initial presentation was more severe than in known types of antenatal Bartter's syndrome, as reflected by an earlier onset of polyhydramnios and labor. All symptoms disappeared spontaneously during follow-up in the infants who survived. We showed that MAGE-D2 affects the expression and function of the sodium chloride cotransporters NKCC2 and NCC (key components of salt reabsorption in the distal renal tubule), possibly through adenylate cyclase and cyclic AMP signaling and a cytoplasmic heat-shock protein.ConclusionsWe found that MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome. MAGE-D2 is essential for fetal renal salt reabsorption, amniotic fluid homeostasis, and the maintenance of pregnancy. (Funded by the University of Groningen and others.).

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