Polyhydramnios, Transient Antenatal Bartter’s Syndrome, andMAGED2Mutations

Abstract

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.).

A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases

“…While most cases of polyhydramnios are mild and result from the gradual increase of amniotic fluid, severe polyhydramnios may result in preterm birth and an increased risk of other perinatal complications [127]. Some of the known causes of polyhydramnios include fetal esophageal atresia and maternal diabetes; however, in 30 to 60% of cases, the cause remains unknown [127–129]. Antenatal Bartter syndrome (OMIM 300971), one of the few Mendelian diseases associated with polyhydramnios, is a rare, often life-threatening autosomal recessive renal tubular disorder characterized by fetal and postnatal polyuria, renal salt wasting, hypercalciuria, hypokalemia [130].…”

“…Recently, Laghmani et al identified mutations in MAGE-D2 that cause X-linked polyhydramnios with prematurity and a transient but severe form of antenatal Bartter syndrome (Figure 6C) [129]. These patients initially exhibited a more severe presentation of antenatal Bartter syndrome with earlier onset of polyhydramnios and preterm labor for male offspring [132].…”

“…Immediately after birth, the infants developed progressive polyuria and severe hypercalciuria; however, within weeks, clinical symptoms spontaneously resolved [132]. Through genetic sequencing of nine families with transient antenatal Bartter syndrome and idiopathic polyhydramnios, the authors identified seven truncating mutations (two nonsense, two frameshift, and three splice-site mutations) and two nontruncating mutations (one missense and one in-frame deletion) in MAGE-D2 [129]. …”

MAGE-D2 and the Regulation of Renal Salt Transporters

“…Now in the Journal, Laghmani et al describe a genetic cause of this transient renal salt-wasting phenotype. 4 All the patients with transient antenatal Bartter's syndrome who were available to the authors for study were male, so the authors predicted the involvement of an X-linked gene. Indeed, by means of whole-exome sequencing and filtering for X-chromosomal variants, Laghmani et al identified in one of these families a loss-offunction mutation in MAGED2, on the X chromosome, that cosegregated with the disorder.…”

The importance of the thick ascending limb of Henle’s loop in renal physiology and pathophysiology

“…70 Recently, cases of some male infants showing features of transient antenatal BS, associated with mutations in the MAGE-D2 gene, have been reported. 71 The gene product is expressed in the DT and in the TAL in both adult and fetal human kidney. Immunostaining studies revealed reduced NKCC2 and Na+-Cl− cotransporter (NCC) apical abundance in one of these patients, with increased NKCC2 cytoplasmic retention.…”