EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies.

Jacky Lo,Richard Warth,Anna-Lena Forst,Anselm A Zdebik

doi:10.3389/fphys.2022.852674

Jacky Lo, Richard Warth + Show 2 more

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https://doi.org/10.3389/fphys.2022.852674

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Abstract

In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

Highlights

K+ Channels: Membrane Proteins Important for LifeK+ channels are indispensable components in the mammalian organism, as they make a crucial contribution to the membrane potential and to electrical processes at the membrane
Kir4.1/Kir5.1: A Sensor of Plasma K+ in the Distal Convoluted Tubule. In addition to this “classical” aldosterone-induced K+ loss, another aspect likely contributes to the hypokalemia in EAST/ SeSAME syndrome: Sorensen and colleagues found that NaCl reabsorption by the thiazide-sensitive NaCl transporter (NCC) is completely put at the service of K+ excretion under certain circumstances: in hyperkalemia, the increased K+ concentration is sensed by distal convoluted tubule (DCT) cells and leads to inhibition of NCC (Sorensen et al, 2013)
The disturbed Na+ and K+ handling in EAST/ SeSAME syndrome results from defects in at least two nephron segments (Wang et al, 2018; Zhang et al, 2018, 2021; Wu et al, 2019a,b): (i) a major consequence of the Kir4.1 defect is the impaired function of the DCT, which leads to flooding of the collecting system (CS) with NaCl due to decreased NCC-mediated NaCl reabsorption

Summary

Introduction

K+ Channels: Membrane Proteins Important for LifeK+ channels are indispensable components in the mammalian organism, as they make a crucial contribution to the membrane potential and to electrical processes at the membrane. These mutations have shown mild gain of function, due to several mechanisms (increased surface expression, open probability and single channel conductance; Sicca et al, 2016).

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