Universität zu Köln

Laghmani, Kamel ORCID: 0000-0002-2167-5766, Beck, Bodo B., Yang, Sung-Sen, Seaayfan, Elie ORCID: 0000-0003-4839-9834, Wenzel, Andrea, Reusch, Bjorn, Vitzthum, Helga, Priem, Dario ORCID: 0000-0002-2527-1101, Demaretz, Sylvie, Bergmann, Klasien, Duin, Leonie K., Goebel, Heike, Mache, Christoph, Thiele, Holger, Bartram, Malte P., Dombret, Carlos, Altmueller, Janine, Nuernberg, Peter, Benzing, Thomas, Levtchenko, Elena, Seyberth, Hannsjoerg W., Klaus, Guenter, Yigit, Goekhan, 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 and Koemhoff, Martin (2016). Polyhydramnios, Transient Antenatal Bartter's Syndrome, and MAGED2 Mutations. N. Engl. J. Med., 374 (19). S. 1853 - 1864. WALTHAM: MASSACHUSETTS MEDICAL SOC. ISSN 1533-4406

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Laghmani, Kamel UNSPECIFIED orcid.org/0000-0002-2167-5766 UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Sung-Sen UNSPECIFIED UNSPECIFIED UNSPECIFIED Seaayfan, Elie UNSPECIFIED orcid.org/0000-0003-4839-9834 UNSPECIFIED Wenzel, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Reusch, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Vitzthum, Helga UNSPECIFIED UNSPECIFIED UNSPECIFIED Priem, Dario UNSPECIFIED orcid.org/0000-0002-2527-1101 UNSPECIFIED Demaretz, Sylvie UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Klasien UNSPECIFIED UNSPECIFIED UNSPECIFIED Duin, Leonie K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goebel, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Mache, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dombret, Carlos UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Levtchenko, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Seyberth, Hannsjoerg W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaus, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lin, Shih-Hua UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmer, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED de Koning, Tom J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Scherjon, Sicco A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlingmann, Karl P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertrand, Mathieu J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Backer, Olivier UNSPECIFIED UNSPECIFIED UNSPECIFIED Konrad, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Koemhoff, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-275764
DOI:	10.1056/NEJMoa1507629
Journal or Publication Title:	N. Engl. J. Med.
Volume:	374
Number:	19
Page Range:	S. 1853 - 1864
Date:	2016
Publisher:	MASSACHUSETTS MEDICAL SOC
Place of Publication:	WALTHAM
ISSN:	1533-4406
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADENYLATE-CYCLASE; COTRANSPORTER; EXPRESSION; RECURRENT; HYPOXIA; AMNIOCENTESES; DEGRADATION; PREGNANCIES; NEPHRON; DISEASE Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27576