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Identification of compound heterozygous KCNJ1 mutations (Encoding ROMK) in a kindred with bartter’s syndrome and a functional analysis of their pathogenicity

Lookup NU author(s): Dr Shalabh Srivastava, Dr Noel Edwards, Dr Ann Marie Hynes, Dr Katrina Wood, Mohamed Al-Hamed, Dr Anna Wroe, Dr David Reaich, Dr Shabbir Moochhala, Professor John SayerORCiD


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© 2013 The Authors. A multiplex family was identified with biochemical and clinical features suggestive of Bartter’s syndrome (BS). The eldest sibling presented with developmental delay and rickets at 4 years of age with evidence of hypercalciuria and hypokalemia. The second sibling presented at 1 year of age with urinary tract infections, polyuria, and polydipsia. The third child was born after a premature delivery with a history of polyhydramnios and neonatal hypocalcemia. Following corrective treatment she also developed hypercalciuria and a hypokalemic metabolic alkalosis. There was evidence of secondary hyperreninemia and hyperaldosteronism in all three siblings consistent with BS. Known BS genes were screened and functional assays of ROMK (alias KCNJ1, Kir1.1) were carried out in Xenopus oocytes. We detected compound heterozygous missense changes in KCNJ1, encoding the potassium channel ROMK. The S219R/L220F mutation was segregated from father and mother, respectively. In silico modeling of the missense mutations suggested deleterious changes. Studies in Xenopus oocytes revealed that both S219R and L220F had a deleterious effect on ROMK-mediated potassium currents. Coinjection to mimic the compound heterozygosity produced a synergistic decrease in channel function and revealed a loss of PKA-dependent stabilization of PIP2 binding. In conclusion, in a multiplex family with BS, we identified compound heterozygous mutations in KCNJ1. Functional studies of ROMK confirmed the pathogenicity of these mutations and defined the mechanism of channel dysfunction. © 2013 American Physiological Society and The Physiological Society.

Publication metadata

Author(s): Srivastava S, Li D, Edwards N, Hynes A-M, Wood K, Al-Hamed M, Wroe AC, Reaich D, Moochhala SH, Welling PA, Sayer JA

Publication type: Article

Publication status: Published

Journal: Physiological Reports

Year: 2013

Volume: 1

Issue: 6

Pages: 1-8

Print publication date: 01/11/2013

Online publication date: 19/11/2013

ISSN (print): 2051-817X

Publisher: American Physiological Society


DOI: 10.1002/phy2.160


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