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Transient antenatal Bartter’s Syndrome and X-linked polyhydramnios: insights from the genetics of a rare condition
nephrology digest
7. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs. delayed initiation of renal replacement therapy in critically ill patients with acute kidney injury. The ELAIN randomized clinical trial. JAMA. 2016;315:2190–2199. 8. Bellomo R, Warrillow SJ, Reade MC. Why we should be wary of single-center trials. Crit Care Med. 2009;37:3114–3119.
9. Vinsonneau C, Camus C, Combes A, et al. Hemodiafe Study Group. Continuous venovenous haemodiafiltration versus intermittent hemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368: 379–385.
acid-base and electrolytes, genetics, water and volume homeostasis
Transient antenatal Bartter’s Syndrome and X-linked polyhydramnios: insights from the genetics of a rare condition Raymond Quigley1 and Jeffrey M. Saland2 The discovery that mutations in MAGED2 cause a rare and transient form of antenatal Bartter’s Syndrome may have implications beyond the very small number of affected families. Understanding the mechanism by which this severe form of Bartter’s Syndrome resolves after birth could also provide new insights into the regulation of tubular transport and the response to tissue hypoxia. Refers to: Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. N Engl J Med. 2016;374:1853–1863. Kidney International (2016) 90, 721–723; http://dx.doi.org/10.1016/j.kint.2016.07.031 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
ver 50 years ago, Bartter described a patient with renal salt wasting and secondary hyperaldosteronism.1 Subsequently, Gitelman et al. described patients with many features similar to Bartter’s Syndrome, except that affected individuals experienced hypocalciuria instead of hypercalciuria.2 Over the subsequent decades, the physiology of the thick ascending limb of the loop of Henle and the distal convoluted tubule became clearer from ion transport studies.3 More recently, the transporters involved in ion transport in these segments have been cloned, leading to the identification of diseasecausing mutations (Figure 1).4–6 Current understanding of the genetics of Bartter’s and Gitelman’s Syndromes is based on the paradigm that a single gene is mutated, resulting in a single protein that does not function properly. In recent work published in the New England Journal of Medicine, Laghmani et al. identified a novel genetic mutation that causes the transcribed protein to alter the function of more than 1 downstream target, causing a combination of Bartter’s and Gitelman’s Syndromes.7 The authors first evaluated 7 families affected by a rare form of severe but transient antenatal Bartter’s Syndrome occurring only in male infants. Whole-exome sequencing in
O
1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA; and 2 Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA Correspondence: Raymond Quigley, UTSW Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9063, USA. E-mail: raymond.quigley@ utsouthwestern.edu
Kidney International (2016) 90, 718–723
a mother and affected son identified a shared truncating mutation in MAGED2, which encodes melanoma-associated antigen D2 (MAGE-D2). Target gene sequencing confirmed that this Xchromosomal variant was present in all surviving affected males in the family and in their mothers. Because 1 pregnancy was complicated by severe polyhydramnios and premature delivery of a stillborn male fetus, the authors also evaluated 11 women with recurrent polyhydramnios complicating pregnancies with male offspring. Sequencing of MAGED2 in these women and in 6 additional families affected by transient antenatal Bartter’s Syndrome identified mutations in 2 of the women and in all 13 affected males.7 The role of MAGE-D2 in fetal renal salt reabsorption and amniotic fluid volume regulation is unknown. The authors showed that MAGE-D2 is expressed in the thick ascending limb and the distal tubule in the developing and adult kidney. In addition, the authors demonstrated that both the loop-diuretic sensitive transporter sodium-potassium-2-chloride co-transporter, which is mutated in a form of Bartter’s Syndrome, as well as sodium chloride co-transporter, which is the transporter affected in Gitelman’s Syndrome, failed to localize 721
nephrology digest
a
b
Aldosterone-sensitive distal nephron
Figure 1 | Depiction of renal tubular cells in the thick ascending limb and distal convoluted tubule. (a) Thick ascending limb of Henle’s loop. (b) Distal convoluted tubule. (c) Aldosterone-sensitive distal nephron. Several forms of Bartter’s Syndrome have been described, caused by mutations in the genes encoding transport proteins in the thick ascending limb. Mutations in the furosemide-sensitive sodium-potassium-2chloride co-transporter (NKCC2) are associated with a severe form of antenatal Bartter’s Syndrome with polyhydramnios. Gitelman’s Syndrome is caused by mutations in the gene encoding the thiazide-sensitive sodium chloride co-transporter (NCC) in the distal convoluted tubule. Newly described mutations in MAGED2 result in mislocalization of both NKCC2 and NCC, causing a severe antenatal salt-losing syndrome in affected male infants. Ca, calcium; Cl, chlorine; K, potassium; Mg, magnesium. Reproduced from Seyberth HW, Schlingmann KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011;26:1789–1802, ª IPNA 2011. ClC-Ka, chloride channel Ka; ClC-Kb, chloride channel Kb; ENaC, epithelial sodium channel; NCCT, sodium chloride co-transporter; ROMK, rat outer medullary potassium channel; TRPM6, transient receptor potential channel M6; TRPVS, transient receptor potential channel VS.
correctly in fetal tubular cells affected by MAGED2 mutations.7 The resulting defect in sodium reabsorption in both the thick ascending limb and the distal tubule is consistent with the severe polyuria seen in affected infants with MAGED2 mutations. The transient nature of the defect is also unclear. Patients with Bartter’s and Gitelman’s Syndromes require lifelong treatment, as the transport proteins are nonfunctional. The authors present evidence that MAGE-D2 interacts with the chaperone protein Hsp40 and with the G protein subunit Gs-alpha, suggesting a potential mechanism for the mislocalization of sodium-potassium-2-chloride co-transporter and sodium chloride co-transporter.7 The latter interaction also suggests that mutations in MAGED2 could impact the generation of cAMP. It is possible that the transient nature of this condition is due to developmental changes in the expression of phosphodiesterase, which catalyzes the degradation of cAMP. Neonatal rabbit collecting ducts have been shown to have high phosphodiesterase activity and thus a decreased response to antidiuretic hormone (ADH), which signals through cAMP.8 As the tubule matures, phosphodiesterase activity 722
declines, allowing the full response to ADH. Thus, if MAGE-D2 reduces cAMP production and phosphodiesterase activity is high in the developing kidney, the tubule may not be able to generate enough cAMP to properly function. As the phosphodiesterase activity decreases, tubular function will normalize. Alternatively, the authors offer an interesting hypothesis that MAGE-D2 has a role in modulating the effect of tissue hypoxia in fetal life and early infancy that becomes less relevant later, possibly as a result of its interaction with Hsp40.7 The study of rare inherited diseases has the potential to impact public health in several important ways. First, these conditions may provide a rare glimpse into the inner workings of a previously unknown physiologic pathway. While the mechanisms by which MAGE-D2 functions with other regulators of fetal tubular transport are unclear, it is not beyond imagination to consider the possibility of a new class of diuretic with the ability to modulate disorders of amniotic fluid, perhaps also with impact in mature kidneys. Second, the identification of genetic variants that are associated with a rare disease may also have implications for common conditions. For example, rare Kidney International (2016) 90, 718–723
nephrology digest
disorders of renal transport have already contributed to our understanding of the natural variation of blood pressure in the general population, and have helped to shape the way in which clinicians consider individual patients with hypertension. Cumulatively, heterozygote carriers of “rare” mutations in salt-wasting genes constituted about 1 in 64 persons in a population-based study, with a large impact on blood pressure.9 Whether MAGED2 mutations have any implications in female carriers is not known. Finally, unlike mutations associated with postnatal conditions, the identification of mutations in MAGED2 that cause antenatal Bartter’s Syndrome may eventually offer insight into how gene switching or other adaptations conspire to make this severe condition so remarkably transient. Can this type of adaptation be understood and harnessed, or even worked backward in other conditions? In addition, if the authors’ speculation is correct and MAGE-D2 has a role in modulating the effect of tissue hypoxia in fetal life and early infancy, variation in MAGED2 or its product may impact the response to renal stress in other settings, such as acute kidney injury. Future studies of the mechanism by which the effects of MAGED2 mutation resolve may offer insight into diverse physiologic and pathophysiologic processes, including regulation of amniotic fluid production, renal electrolyte transport,
Kidney International (2016) 90, 718–723
and response to and recovery from acute kidney injury. DISCLOSURE All the authors declared no competing interests. REFERENCES 1. Bartter FC, Pronove P, Gill JR Jr., Maccardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med. 1962;33:811–828. 2. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians. 1966;79: 221–235. 3. Greger R. Ion transport mechanisms in thick ascending limb of Henle’s loop of mammalian nephron. Physiol Rev. 1985;65:760–797. 4. Simon DB, Karet FE, Hamdan JM, et al. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996;13:183–188. 5. Simon DB, Karet FE, Rodriguez-Soriano J, et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the Kþ channel, ROMK. Nat Genet. 1996;14:152–156. 6. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazidesensitive Na-Cl cotransporter. Nat Genet. 1996;12:24–30. 7. Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. N Engl J Med. 2016;374:1853–1863. 8. Quigley R, Chakravarty S, Baum M. Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity. Am J Physiol Renal Physiol. 2004;286:F317–F322. 9. Ji W, Foo JN, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–599.
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7. Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs. delayed initiation of renal replacement therapy in critically ill patients with acute kidney injury. The ELAIN randomized clinical trial. JAMA. 2016;315:2190–2199. 8. Bellomo R, Warrillow SJ, Reade MC. Why we should be wary of single-center trials. Crit Care Med. 2009;37:3114–3119.
9. Vinsonneau C, Camus C, Combes A, et al. Hemodiafe Study Group. Continuous venovenous haemodiafiltration versus intermittent hemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368: 379–385.
acid-base and electrolytes, genetics, water and volume homeostasis
Transient antenatal Bartter’s Syndrome and X-linked polyhydramnios: insights from the genetics of a rare condition Raymond Quigley1 and Jeffrey M. Saland2 The discovery that mutations in MAGED2 cause a rare and transient form of antenatal Bartter’s Syndrome may have implications beyond the very small number of affected families. Understanding the mechanism by which this severe form of Bartter’s Syndrome resolves after birth could also provide new insights into the regulation of tubular transport and the response to tissue hypoxia. Refers to: Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. N Engl J Med. 2016;374:1853–1863. Kidney International (2016) 90, 721–723; http://dx.doi.org/10.1016/j.kint.2016.07.031 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
ver 50 years ago, Bartter described a patient with renal salt wasting and secondary hyperaldosteronism.1 Subsequently, Gitelman et al. described patients with many features similar to Bartter’s Syndrome, except that affected individuals experienced hypocalciuria instead of hypercalciuria.2 Over the subsequent decades, the physiology of the thick ascending limb of the loop of Henle and the distal convoluted tubule became clearer from ion transport studies.3 More recently, the transporters involved in ion transport in these segments have been cloned, leading to the identification of diseasecausing mutations (Figure 1).4–6 Current understanding of the genetics of Bartter’s and Gitelman’s Syndromes is based on the paradigm that a single gene is mutated, resulting in a single protein that does not function properly. In recent work published in the New England Journal of Medicine, Laghmani et al. identified a novel genetic mutation that causes the transcribed protein to alter the function of more than 1 downstream target, causing a combination of Bartter’s and Gitelman’s Syndromes.7 The authors first evaluated 7 families affected by a rare form of severe but transient antenatal Bartter’s Syndrome occurring only in male infants. Whole-exome sequencing in
O
1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA; and 2 Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA Correspondence: Raymond Quigley, UTSW Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9063, USA. E-mail: raymond.quigley@ utsouthwestern.edu
Kidney International (2016) 90, 718–723
a mother and affected son identified a shared truncating mutation in MAGED2, which encodes melanoma-associated antigen D2 (MAGE-D2). Target gene sequencing confirmed that this Xchromosomal variant was present in all surviving affected males in the family and in their mothers. Because 1 pregnancy was complicated by severe polyhydramnios and premature delivery of a stillborn male fetus, the authors also evaluated 11 women with recurrent polyhydramnios complicating pregnancies with male offspring. Sequencing of MAGED2 in these women and in 6 additional families affected by transient antenatal Bartter’s Syndrome identified mutations in 2 of the women and in all 13 affected males.7 The role of MAGE-D2 in fetal renal salt reabsorption and amniotic fluid volume regulation is unknown. The authors showed that MAGE-D2 is expressed in the thick ascending limb and the distal tubule in the developing and adult kidney. In addition, the authors demonstrated that both the loop-diuretic sensitive transporter sodium-potassium-2-chloride co-transporter, which is mutated in a form of Bartter’s Syndrome, as well as sodium chloride co-transporter, which is the transporter affected in Gitelman’s Syndrome, failed to localize 721
nephrology digest
a
b
Aldosterone-sensitive distal nephron
Figure 1 | Depiction of renal tubular cells in the thick ascending limb and distal convoluted tubule. (a) Thick ascending limb of Henle’s loop. (b) Distal convoluted tubule. (c) Aldosterone-sensitive distal nephron. Several forms of Bartter’s Syndrome have been described, caused by mutations in the genes encoding transport proteins in the thick ascending limb. Mutations in the furosemide-sensitive sodium-potassium-2chloride co-transporter (NKCC2) are associated with a severe form of antenatal Bartter’s Syndrome with polyhydramnios. Gitelman’s Syndrome is caused by mutations in the gene encoding the thiazide-sensitive sodium chloride co-transporter (NCC) in the distal convoluted tubule. Newly described mutations in MAGED2 result in mislocalization of both NKCC2 and NCC, causing a severe antenatal salt-losing syndrome in affected male infants. Ca, calcium; Cl, chlorine; K, potassium; Mg, magnesium. Reproduced from Seyberth HW, Schlingmann KP. Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects. Pediatr Nephrol. 2011;26:1789–1802, ª IPNA 2011. ClC-Ka, chloride channel Ka; ClC-Kb, chloride channel Kb; ENaC, epithelial sodium channel; NCCT, sodium chloride co-transporter; ROMK, rat outer medullary potassium channel; TRPM6, transient receptor potential channel M6; TRPVS, transient receptor potential channel VS.
correctly in fetal tubular cells affected by MAGED2 mutations.7 The resulting defect in sodium reabsorption in both the thick ascending limb and the distal tubule is consistent with the severe polyuria seen in affected infants with MAGED2 mutations. The transient nature of the defect is also unclear. Patients with Bartter’s and Gitelman’s Syndromes require lifelong treatment, as the transport proteins are nonfunctional. The authors present evidence that MAGE-D2 interacts with the chaperone protein Hsp40 and with the G protein subunit Gs-alpha, suggesting a potential mechanism for the mislocalization of sodium-potassium-2-chloride co-transporter and sodium chloride co-transporter.7 The latter interaction also suggests that mutations in MAGED2 could impact the generation of cAMP. It is possible that the transient nature of this condition is due to developmental changes in the expression of phosphodiesterase, which catalyzes the degradation of cAMP. Neonatal rabbit collecting ducts have been shown to have high phosphodiesterase activity and thus a decreased response to antidiuretic hormone (ADH), which signals through cAMP.8 As the tubule matures, phosphodiesterase activity 722
declines, allowing the full response to ADH. Thus, if MAGE-D2 reduces cAMP production and phosphodiesterase activity is high in the developing kidney, the tubule may not be able to generate enough cAMP to properly function. As the phosphodiesterase activity decreases, tubular function will normalize. Alternatively, the authors offer an interesting hypothesis that MAGE-D2 has a role in modulating the effect of tissue hypoxia in fetal life and early infancy that becomes less relevant later, possibly as a result of its interaction with Hsp40.7 The study of rare inherited diseases has the potential to impact public health in several important ways. First, these conditions may provide a rare glimpse into the inner workings of a previously unknown physiologic pathway. While the mechanisms by which MAGE-D2 functions with other regulators of fetal tubular transport are unclear, it is not beyond imagination to consider the possibility of a new class of diuretic with the ability to modulate disorders of amniotic fluid, perhaps also with impact in mature kidneys. Second, the identification of genetic variants that are associated with a rare disease may also have implications for common conditions. For example, rare Kidney International (2016) 90, 718–723
nephrology digest
disorders of renal transport have already contributed to our understanding of the natural variation of blood pressure in the general population, and have helped to shape the way in which clinicians consider individual patients with hypertension. Cumulatively, heterozygote carriers of “rare” mutations in salt-wasting genes constituted about 1 in 64 persons in a population-based study, with a large impact on blood pressure.9 Whether MAGED2 mutations have any implications in female carriers is not known. Finally, unlike mutations associated with postnatal conditions, the identification of mutations in MAGED2 that cause antenatal Bartter’s Syndrome may eventually offer insight into how gene switching or other adaptations conspire to make this severe condition so remarkably transient. Can this type of adaptation be understood and harnessed, or even worked backward in other conditions? In addition, if the authors’ speculation is correct and MAGE-D2 has a role in modulating the effect of tissue hypoxia in fetal life and early infancy, variation in MAGED2 or its product may impact the response to renal stress in other settings, such as acute kidney injury. Future studies of the mechanism by which the effects of MAGED2 mutation resolve may offer insight into diverse physiologic and pathophysiologic processes, including regulation of amniotic fluid production, renal electrolyte transport,
Kidney International (2016) 90, 718–723
and response to and recovery from acute kidney injury. DISCLOSURE All the authors declared no competing interests. REFERENCES 1. Bartter FC, Pronove P, Gill JR Jr., Maccardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med. 1962;33:811–828. 2. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians. 1966;79: 221–235. 3. Greger R. Ion transport mechanisms in thick ascending limb of Henle’s loop of mammalian nephron. Physiol Rev. 1985;65:760–797. 4. Simon DB, Karet FE, Hamdan JM, et al. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. 1996;13:183–188. 5. Simon DB, Karet FE, Rodriguez-Soriano J, et al. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the Kþ channel, ROMK. Nat Genet. 1996;14:152–156. 6. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazidesensitive Na-Cl cotransporter. Nat Genet. 1996;12:24–30. 7. Laghmani K, Beck BB, Yang SS, et al. Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations. N Engl J Med. 2016;374:1853–1863. 8. Quigley R, Chakravarty S, Baum M. Antidiuretic hormone resistance in the neonatal cortical collecting tubule is mediated in part by elevated phosphodiesterase activity. Am J Physiol Renal Physiol. 2004;286:F317–F322. 9. Ji W, Foo JN, O’Roak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:592–599.
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