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Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED2 mutations

(2016) NEW ENGLAND JOURNAL OF MEDICINE. 374(19). p.1853-1863
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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.
Keywords
ADENYLATE-CYCLASE, COTRANSPORTER, EXPRESSION, RECURRENT, HYPOXIA, AMNIOCENTESES, DEGRADATION, PREGNANCIES, NEPHRON, DISEASE

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Citation

Please use this url to cite or link to this publication:

Chicago
Laghmani, Kamel, Bodo B Beck, Sung-Sen Yang, Elie Seaayfan, Andrea Wenzel, Björn Reusch, Helga Vitzthum, et al. 2016. “Polyhydramnios, Transient Antenatal Bartter’s Syndrome, and MAGED2 Mutations.” New England Journal of Medicine 374 (19): 1853–1863.
APA
Laghmani, K., Beck, B. B., Yang, S.-S., Seaayfan, E., Wenzel, A., Reusch, B., Vitzthum, H., et al. (2016). Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. NEW ENGLAND JOURNAL OF MEDICINE, 374(19), 1853–1863.
Vancouver
1.
Laghmani K, Beck BB, Yang S-S, Seaayfan E, Wenzel A, Reusch B, et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. NEW ENGLAND JOURNAL OF MEDICINE. 2016;374(19):1853–63.
MLA
Laghmani, Kamel, Bodo B Beck, Sung-Sen Yang, et al. “Polyhydramnios, Transient Antenatal Bartter’s Syndrome, and MAGED2 Mutations.” NEW ENGLAND JOURNAL OF MEDICINE 374.19 (2016): 1853–1863. Print.
@article{8522578,
  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.},
  author       = {Laghmani, Kamel and Beck, Bodo B and Yang, Sung-Sen and Seaayfan, Elie and Wenzel, Andrea and Reusch, Bj{\"o}rn and Vitzthum, Helga and Priem, Dario and Demaretz, Sylvie and Bergmann, Klasien and Duin, Leonie K and G{\"o}bel, Heike and Mache, Christoph and Thiele, Holger and Bartram, Malte P and Dombret, Carlos and Altm{\"u}ller, Janine and N{\"u}rnberg, Peter and Benzing, Thomas and Levtchenko, Elena and Seyberth, Hannsj{\"o}rg W and Klaus, G{\"u}nter and Yigit, G{\"o}khan and Lin, Shih-Hua and Timmer, Albert and de Koning, Tom J and Scherjon, Sicco A and Schlingmann, Karl P and Bertrand, Mathieu and Rinschen, Markus M and de Backer, Olivier and Konrad, Martin and K{\"o}mhoff, Martin},
  issn         = {0028-4793},
  journal      = {NEW ENGLAND JOURNAL OF MEDICINE},
  keyword      = {ADENYLATE-CYCLASE,COTRANSPORTER,EXPRESSION,RECURRENT,HYPOXIA,AMNIOCENTESES,DEGRADATION,PREGNANCIES,NEPHRON,DISEASE},
  language     = {eng},
  number       = {19},
  pages        = {1853--1863},
  title        = {Polyhydramnios, transient antenatal Bartter's syndrome, and MAGED2 mutations},
  url          = {http://dx.doi.org/10.1056/NEJMoa1507629},
  volume       = {374},
  year         = {2016},
}

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