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KCNJ10 Gene Mutations Causing EAST Syndrome (Epilepsy, Ataxia, Sensorineural Deafness, and Tubulopathy) Disrupt Channel Function

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KCNJ10 Gene Mutations Causing EAST Syndrome (Epilepsy, Ataxia, Sensorineural Deafness, and Tubulopathy) Disrupt Channel Function KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function Markus Reicholda,1, Anselm A. Zdebikb,1, Evelyn Lieberera,1, Markus Rapediusc,1, Katharina Schmidta, Sascha Bandulika, Christina Sternera, Ines Tegtmeiera, David Pentona, Thomas Baukrowitzc, Sally-Anne Hultond, Ralph Witzgalle, Bruria Ben-Zeevf, Alexander J. Howieg, Robert Kletab,1, Detlef Bockenhauerb,1, and Richard Wartha,1,2 aDepartment of Physiology, University of Regensburg, 93053 Regensburg, Germany; bDepartments of Physiology and Medicine and Institute of Child Health and gDepartment of Pathology, University College London, London NW3 2PF, United Kingdom; cDepartment of Physiology, University Hospital Jena, 07743 Jena, Germany; dBirmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom; eDepartment of Anatomy, University of Regensburg, 93053 Regensburg, Germany; and fPediatric Neurology Unit, Edmond and Lilly Safra Children’s Hospital, Sheba Medical Center, Ramat-Gan 46425, Israel Edited* by Gerhard Giebisch, Yale University School of Medicine, New Haven, CT, and approved June 30, 2010 (received for review March 9, 2010) Mutations of the KCNJ10 (Kir4.1)K+ channel underlie autosomal Kcnj16 (Kir5.1) are also found in the cortical thick ascending limb recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wast- (7). Kcnj10 and Kcnj16 are localized in the basolateral membrane, ing) renal tubulopathy (EAST) syndrome. We investigated the local- where they establish the hyperpolarized membrane voltage needed − ization of KCNJ10 and the homologous KCNJ16 in kidney and the for electrogenic ion transport (e.g., Cl exit and Na+-coupled Ca2+ functional consequences of KCNJ10 mutations found in our and Mg2+ export) (8). Additionally, KCNJ10/KCNJ16 activity is patients with EAST syndrome. Kcnj10 and Kcnj16 were found in required for Na+/K+-ATPase pump activity. Basolateral Na+/K+- the basolateral membrane of mouse distal convoluted tubules, con- ATPases take up K+ from the narrow space of the basolateral necting tubules, and cortical collecting ducts. In the human kidney, invaginations of the plasma membrane. During Na+/K+-ATPase KCNJ10 staining was additionally observed in the basolateral mem- activity, basolateral K+ becomes a rate-limiting factor limiting fur- brane of the cortical thick ascending limb of Henle’s loop. EM of + fl + ther pump activity. K ef ux through KCNJ10/KCNJ16 allows K PHYSIOLOGY distal tubular cells of a patient with EAST syndrome showed to recycle, and thereby permits continuous Na+/K+-ATPase activity reduced basal infoldings in this nephron segment, which likely [so-called “pump-leak coupling” (9–12)]. Although KCNJ10 and fl re ects the morphological consequences of the impaired salt reab- KCNJ16 are not the only K+ channels expressed in these nephron sorption capacity. When expressed in CHO and HEK293 cells, the segments, they appear to be critical for the pump-leak coupling, − − KCNJ10 mutations R65P, G77R, and R175Q caused a marked impair- because human patients and Kcnj10 / mice display deficits of the ment of channel function. R199X showed complete loss of function. reabsorptivefunction inthenephron segments mentioned above(2). Single-channel analysis revealed a strongly reduced mean open In this study, we have investigated the localization of KCNJ10 time. Qualitatively similar results were obtained with coexpression in mouse and human kidney and the functional consequences of of KCNJ10/KCNJ16, suggesting a dominance of KCNJ10 function in mutations of KCNJ10 that we have found in our patients with EAST native renal KCNJ10/KCNJ16 heteromers. The decrease in the cur- syndrome. Notably, the renal biopsy of a patient with EAST syn- rent of R65P and R175Q was mainly caused by a remarkable shift of drome disclosed loss of basolateral infoldings of distal convoluted pH sensitivity to the alkaline range. In summary, EAST mutations of tubular cells as a morphological correlate of the impaired transport KCNJ10 lead to impaired channel function and structural changes in function resulting in salt wasting. The KCNJ10 mutations G77R distal convoluted tubules. Intriguingly, the metabolic alkalosis pres- and R199X showed almost complete loss of function. The R65P ent in patients carrying the R65P mutation possibly improves re- sidual function of KCNJ10, which shows higher activity at mutation and the newly described R175Q mutation resulted in alkaline pH. mutated proteins with small residual function and substantially changed pH sensitivity with IC50 values in the alkaline range. The Bartter | Gitelman | kidney | Kir4.1 | SeSAME changed pH sensitivity in these mutations may therefore have implications for the treatment of patients carrying these mutations. he kidneys play a key role in electrolyte and water homeostasis Results fi Tof the body. In renal salt-wasting disorders, speci c transport Localization of KCNJ10 and KCNJ16 in Mouse and Human Kidney. functions of tubular epithelial cells are impaired. Defects of salt KCNJ10 and KCNJ16 are inwardly rectifying K+ channels ex- transport in the thick ascending loop of Henle and the distal con- pressed in renal tubules. It has been proposed that both channels ’ voluted tubule underlie the salt-wasting states observed in Bartter s form heterotetramers to build functional channels in native tissues. syndrome(s) and Gitelman’s syndrome, respectively (1). We and others described a unique autosomal recessive form of Gitelman- like renal salt wasting caused by mutations in the potassium channel Author contributions: M. Reichold, A.A.Z., T.B., S.-A.H., B.B.-Z., A.J.H., R.K., D.B., and R. KCNJ10 (2, 3). KNCJ10 (Kir4.1) is expressed in various tissues, Warth designed research; M. Reichold, A.A.Z., E.L., M. Rapedius, K.S., S.B., C.S., I.T., D.P., including brain, inner ear, eye, and kidney (4, 5). Patients suffering T.B., S.-A.H., B.B.-Z., A.J.H., R.K., and D.B. performed research; M. Reichold, A.A.Z., E.L., M. from KCNJ10 mutations display a complex combination of features Rapedius, K.S., S.B., C.S., I.T., T.B., S.-A.H., R. Witzgall, B.B.-Z., A.J.H., R.K., D.B., and R. Warth analyzed data; and M. Reichold, A.A.Z., T.B., A.J.H., R.K., D.B., and R. Warth wrote we called EAST syndrome: epilepsy, ataxia, sensorineural deaf- the paper. ness, and (a salt-wasting) renal tubulopathy. The renal features The authors declare no conflict of interest. resemble those of Gitelman’s syndrome and comprise urinary Na+ *This Direct Submission article had a prearranged editor. loss, activation of the renin-angiotensin-aldosterone system, hy- 1M. Reichold., A.A.Z., E.L., M. Rapedius, R.K., D.B., and R. Warth contributed equally to pokalemic metabolic alkalosis, hypomagnesemia, and hypo- this work. calciuria (2). 2To whom correspondence should be addressed. E-mail: richard.warth@vkl. In C57BL6 mouse kidney, Kcnj10 is expressed in distal convo- uni-regensburg.de. luted tubules starting from the macula densa down to the early This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. cortical collecting duct (2, 6). In CD1 mice, Kcnj10 and related 1073/pnas.1003072107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1003072107 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 We therefore examined the renal localization of both channel proteins by immunofluorescence. As described previously, in C57BL6 mouse kidney, Kcnj10 labeling was found in early and late distal convoluted tubules, starting sharply at the macula densa, and also in connecting tubules and early cortical collecting ducts. Aquaporin-2-negative intercalated cells were not labeled by the KCNJ10 antibody. Using consecutive sections, Kcnj16 showed a distribution similar to Kcnj10, suggesting that both channels could form heterotetramers in native tubular cells (Fig. 1 A–F). In human kidney, localization distal to the macula densa was similar to that observed in C57BL6 mouse kidney. However, in addition to this, KCNJ10 was found in cortical thick ascending limbs, as evidenced by − staining of Na+2Cl K+ cotransporter (NKCC2) in consecutive sections (Fig. 1 G and H). Changes in the Distal Convoluted Tubule in EAST Syndrome. Patients with EAST syndrome display renal salt wasting and electrolyte disturbances that resemble the clinical features of impaired distal tubular salt transport in Gitelman’s syndrome. We investigated the distal tubular morphology of a patient who had EAST syn- drome using renal biopsy material. EM of the distal convoluted tubule revealed a decreased number of mitochondria and re- duction of basolateral infoldings (Fig. 2). These morphological data confirm the concept of reduced reabsorptive capacity of the distal convoluted tubule when basolateral K+ efflux is impaired. Fig. 2. Morphological changes of distal convoluted tubule cells in EAST syndrome. Electron micrographs of distal convoluted tubule cells of a control (A) and an EAST patient (B). The patient with EAST syndrome shows a de- creased number of mitochondria and reduction of basolateral infoldings (arrows). The apparent difference in the density of mitochondria between A and B is attributable to slight differences in fixation. (Scale bars: 2 μm.) Functional Consequences of KCNJ10 Mutations Found in EAST Syndrome. We have identified mutations of the potassium channel KCNJ10 that are causative for a renal salt-wasting disease, EAST syndrome. A first set of experiments using Xenopus oocytes sug- gested a functional deficit of two disease-related KCNJ10 mutations (2). In this study, we performed a more detailed electrophysiological analysis of four KCNJ10 mutations found in our patients with EAST syndrome: c.194G > C resulting in p.R65P, c.229G > C resulting in p.G77R, c.524G > A resulting in p.R175Q, and c.595C > Tresulting in p.R199X. The KCNJ10 mutation p.R175Q has not been de- scribed previously. Fig. 3A shows a scheme of human KCNJ10 and the localization of the above-mentioned mutations. The mutated KCNJ10 channels were heterologously expressed in CHO cells. The membrane voltage of cells expressing human WT KCNJ10 Fig.
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