Although virtually all forms of antenatal Bartter syndrome persist, some cases are transient with spontaneous resolution of symptoms shortly after birth. Kömhoff explains that his interest in transient antenatal Bartter syndrome developed after encountering a family in which three pregnancies with male offspring were complicated by early-onset polyhydramnios and prematurity. One fetus died whereas the two living infants had a Bartter-like syndrome, with substantial salt wasting and polyuria that resolved within a few weeks. “Recognition of a possible X-linked transmission in this as well as other families led to X chromosome exome sequencing and the identification of mutations in MAGED2 in 13 individuals from seven families,” he says. “In addition, we identified MAGED2-mutations in two additional families from a cohort of women who had experienced idiopathic polyhydramnios but with no evidence of transient Bartter syndrome in their male offspring.”
Using immunohistochemistry, the researchers examined the renal expression of NKCC2, NCC and uromodulin in the deceased fetus from the case family. “This analysis showed intracellular retention and reduced apical expression of the sodium transporters, whereas uromodulin stained normally,” says Kömhoff. “The effects of knockdown and overexpression of MAGED2 on the heterologous expression of the transporters in HEK296 cells confirmed our immunohistochemical findings.” To determine how MAGED2 affects expression of the transporters, Kömhoff and colleagues compared the interactome of wild-type and mutant MAGED2, identifying differential binding of the cytoplasmic chaperone Hsp40 and Gsα to the two forms of MAGED2. “Altered Hsp40 and Gsα activity fits with intracellular retention and reduced apical expression of the two transporters,” notes Kömhoff.
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