Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity

Physiological Reports

Shalabh Srivastava²  Dimin Li¹  Noel Edwards²  Ann-M. Hynes²  Katrina Wood³  Mohamed Al-Hamed²  Anna C. Wroe⁴  David Reaich⁴  Shabbir H. Moochhala⁵  Paul A. Welling¹ 

[1] Department of Physiology, University of Maryland Medical School, Baltimore, Maryland;Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, U.K.;Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, U.K.;South Tees NHS Foundation Trust, Middlesbrough, U.K.;UCL Centre for Nephrology, Royal Free Hospital, London, U.K.

关键词: Hypercalciuria;    hypokalemia;    KCNJ1;    Kir1.1;    missense mutation;    potassium;    ROMK;    salt wasting;   

DOI  :  10.1002/phy2.160

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY   
© 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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