Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations

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 LevtchenkoHannsjörg 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, Martin Kömhoff

Research output: Contribution to journalArticle

Abstract

Background Three 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. Methods To 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. Results We 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. Conclusions We 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.).

Original languageEnglish
JournalThe New England journal of medicine
DOIs
Publication statusPublished - 2016

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Bartter Syndrome
Polyhydramnios
Melanoma-Specific Antigens
Mutation
Fetus
Salts
Sodium Chloride Symporters
Distal Kidney Tubule
Pregnancy Maintenance
Exome
Labor Onset
Polyuria
X Chromosome
Amniotic Fluid
Heat-Shock Proteins
DNA Sequence Analysis
Adenylyl Cyclases
Cyclic AMP
Proteins
Homeostasis

Cite this

Laghmani, K., Beck, B. B., Yang, S-S., Seaayfan, E., Wenzel, A., Reusch, B., ... Kömhoff, M. (2016). Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. The New England journal of medicine. https://doi.org/10.1056/NEJMoa1507629
Laghmani, Kamel ; Beck, Bodo B ; Yang, Sung-Sen ; Seaayfan, Elie ; Wenzel, Andrea ; Reusch, Björn ; Vitzthum, Helga ; Priem, Dario ; Demaretz, Sylvie ; Bergmann, Klasien ; Duin, Leonie K ; Göbel, Heike ; Mache, Christoph ; Thiele, Holger ; Bartram, Malte P ; Dombret, Carlos ; Altmüller, Janine ; Nürnberg, Peter ; Benzing, Thomas ; Levtchenko, Elena ; Seyberth, Hannsjörg W ; Klaus, Günter ; Yigit, Gökhan ; Lin, Shih-Hua ; Timmer, Albert ; de Koning, Tom J ; Scherjon, Sicco A ; Schlingmann, Karl P ; Bertrand, Mathieu J M ; Rinschen, Markus M ; de Backer, Olivier ; Konrad, Martin ; Kömhoff, Martin. / Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. In: The New England journal of medicine. 2016.
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abstract = "Background Three 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. Methods To 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. Results We 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. Conclusions We 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.).",
author = "Kamel Laghmani and Beck, {Bodo B} and Sung-Sen Yang and Elie Seaayfan and Andrea Wenzel and Bj{\"o}rn Reusch and Helga Vitzthum and Dario Priem and Sylvie Demaretz and Klasien Bergmann and Duin, {Leonie K} and Heike G{\"o}bel and Christoph Mache and Holger Thiele and Bartram, {Malte P} and Carlos Dombret and Janine Altm{\"u}ller and Peter N{\"u}rnberg and Thomas Benzing and Elena Levtchenko and Seyberth, {Hannsj{\"o}rg W} and G{\"u}nter Klaus and G{\"o}khan Yigit and Shih-Hua Lin and Albert Timmer and {de Koning}, {Tom J} and Scherjon, {Sicco A} and Schlingmann, {Karl P} and Bertrand, {Mathieu J M} and Rinschen, {Markus M} and {de Backer}, Olivier and Martin Konrad and Martin K{\"o}mhoff",
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doi = "10.1056/NEJMoa1507629",
language = "English",
journal = "The New England journal of medicine",
issn = "0028-4793",
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Laghmani, K, Beck, BB, Yang, S-S, Seaayfan, E, Wenzel, A, Reusch, B, Vitzthum, H, Priem, D, Demaretz, S, Bergmann, K, Duin, LK, Göbel, H, Mache, C, Thiele, H, Bartram, MP, Dombret, C, Altmüller, J, Nürnberg, P, Benzing, T, Levtchenko, E, Seyberth, HW, Klaus, G, Yigit, G, Lin, S-H, Timmer, A, de Koning, TJ, Scherjon, SA, Schlingmann, KP, Bertrand, MJM, Rinschen, MM, de Backer, O, Konrad, M & Kömhoff, M 2016, 'Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations', The New England journal of medicine. https://doi.org/10.1056/NEJMoa1507629

Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. / Laghmani, Kamel; Beck, Bodo B; Yang, Sung-Sen; Seaayfan, Elie; Wenzel, Andrea; Reusch, Björn; Vitzthum, Helga; Priem, Dario; Demaretz, Sylvie; Bergmann, Klasien; Duin, Leonie K; Göbel, Heike; Mache, Christoph; Thiele, Holger; Bartram, Malte P; Dombret, Carlos; Altmüller, Janine; Nürnberg, Peter; Benzing, Thomas; Levtchenko, Elena; Seyberth, Hannsjörg W; Klaus, Günter; Yigit, Gökhan; Lin, Shih-Hua; Timmer, Albert; de Koning, Tom J; Scherjon, Sicco A; Schlingmann, Karl P; Bertrand, Mathieu J M; Rinschen, Markus M; de Backer, Olivier; Konrad, Martin; Kömhoff, Martin.

In: The New England journal of medicine, 2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations

AU - Laghmani, Kamel

AU - Beck, Bodo B

AU - Yang, Sung-Sen

AU - Seaayfan, Elie

AU - Wenzel, Andrea

AU - Reusch, Björn

AU - Vitzthum, Helga

AU - Priem, Dario

AU - Demaretz, Sylvie

AU - Bergmann, Klasien

AU - Duin, Leonie K

AU - Göbel, Heike

AU - Mache, Christoph

AU - Thiele, Holger

AU - Bartram, Malte P

AU - Dombret, Carlos

AU - Altmüller, Janine

AU - Nürnberg, Peter

AU - Benzing, Thomas

AU - Levtchenko, Elena

AU - Seyberth, Hannsjörg W

AU - Klaus, Günter

AU - Yigit, Gökhan

AU - Lin, Shih-Hua

AU - Timmer, Albert

AU - de Koning, Tom J

AU - Scherjon, Sicco A

AU - Schlingmann, Karl P

AU - Bertrand, Mathieu J M

AU - Rinschen, Markus M

AU - de Backer, Olivier

AU - Konrad, Martin

AU - Kömhoff, Martin

PY - 2016

Y1 - 2016

N2 - Background Three 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. Methods To 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. Results We 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. Conclusions We 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.).

AB - Background Three 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. Methods To 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. Results We 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. Conclusions We 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.).

U2 - 10.1056/NEJMoa1507629

DO - 10.1056/NEJMoa1507629

M3 - Article

JO - The New England journal of medicine

JF - The New England journal of medicine

SN - 0028-4793

ER -