Polyhydramnios, transient antenatal bartter's syndrome, and MAGED2 mutations
(2016) In New England Journal of Medicine 374(19). p.1853-1863- 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 wholeexome 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.... (More)
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 wholeexome 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.)
(Less)
- author
- publishing date
- 2016-05-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- New England Journal of Medicine
- volume
- 374
- issue
- 19
- pages
- 11 pages
- publisher
- Massachusetts Medical Society
- external identifiers
-
- scopus:84966577658
- pmid:27120771
- ISSN
- 0028-4793
- DOI
- 10.1056/NEJMoa1507629
- language
- English
- LU publication?
- no
- id
- 76af82d1-eada-4507-afd2-19e4fd7b0a1f
- date added to LUP
- 2020-02-26 09:56:36
- date last changed
- 2024-06-26 11:56:17
@article{76af82d1-eada-4507-afd2-19e4fd7b0a1f,
abstract = {{<p>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 wholeexome 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.)</p>}},
author = {{Laghmani, Kamel and Beck, Bodo B. and Yang, Sung Sen and Seaayfan, Elie and Wenzel, Andrea and Reusch, Bjorn and Vitzthum, Helga and Priem, Dario and Demaretz, Sylvie and Bergmann, Klasien and Duin, Leonie K. and Gobel, Heike and Mache, Christoph and Thiele, Holger and Bartram, Malte P. and Dombret, Carlos and Altmuller, Janine and Nurnberg, Peter and Benzing, Thomas and Levtchenko, Elena and Seyberth, Hannsjorg W. and Klaus, Gunter and Yigit, Gokhan and Lin, Shih Hua and Timmer, Albert 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 Konrad, Martin and Komhoff, Martin}},
issn = {{0028-4793}},
language = {{eng}},
month = {{05}},
number = {{19}},
pages = {{1853--1863}},
publisher = {{Massachusetts Medical Society}},
series = {{New England Journal of Medicine}},
title = {{Polyhydramnios, transient antenatal bartter's syndrome, and MAGED2 mutations}},
url = {{http://dx.doi.org/10.1056/NEJMoa1507629}},
doi = {{10.1056/NEJMoa1507629}},
volume = {{374}},
year = {{2016}},
}