Biallelic loss-of-function variants in KCNJ16 presenting with hypokalemic metabolic acidosis

Bryn D Webb,Bruce D Gelb,Lisa Satlin,Hilary Hotchkiss,Pankaj Prasun

doi:10.1038/s41431-021-00883-0

Abstract

KCNJ16 encodes Kir5.1 and acts in combination with Kir4.1, encoded by KCNJ10, to form an inwardly rectifying K+ channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+ recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+ handling. Previous work has shown that Kcnj16−/− mice and SSKcnj16−/− rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants in KCNJ16 by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.

Highlights

Basolateral K+ channels in the aldosterone-sensitive distal nephron (ASDN), including the distal convoluted tubule (DCT) and the cortical collecting duct, are essential for controlling basolateral membrane potential and in recycling of K+ taken up into the cell by the basolateral Na-KATPase, the ubiquitous pump that drives transepithelial Na+ absorption [1]
The Kir4.1/Kir5.1 channel, the predominant basolateral K+ channel in ASDN, is an inwardly rectifying potassium channel that is exquisitely sensitive to intracellular pH within the physiological range
The proband was a grossly nondysmorphic 2-year-old female, height at the 53rd percentile and weight at the 56th percentile, daughter of a consanguineous union who was born at full term by normal standard vaginal delivery and presented with dehydration and acidosis precipitated by minor illnesses

Summary

Introduction

Basolateral K+ channels in the aldosterone-sensitive distal nephron (ASDN), including the distal convoluted tubule (DCT) and the cortical collecting duct, are essential for controlling basolateral membrane potential and in recycling of K+ taken up into the cell by the basolateral Na-KATPase, the ubiquitous pump that drives transepithelial Na+ absorption [1]. KCNJ16 encodes Kir5.1, which itself does not conduct K+, but which forms a heterotetramer with Kir4.1, encoded by KCNJ10 [2]. The Kir4.1/Kir5.1 channel, the predominant basolateral K+ channel in ASDN, is an inwardly rectifying potassium channel that is exquisitely sensitive to intracellular pH within the physiological range

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Conclusion