We report a unique constellation of multiorgan signs and symptoms — epilepsy, ataxia, sensorineural deafness, and a renal salt-losing tubulopathy, which we call the EAST syndrome — associated with mutant KCNJ10. The multiplicity of symptoms reveals the important role of KCNJ10 in these various organ systems.
We detected homozygous missense mutations in our patients that substantially impair the function of KCNJ10,
a potassium-channel gene. The identified mutations reside in a highly conserved area — namely, a transmembrane region that probably determines the overall function of this type of channel.27
Indeed, in a heterologous expression system, these mutations nearly abrogated potassium current. Mice lacking this potassium channel died as neonates; homozygous nonsense mutations or gene deletions of this channel may also be fatal in humans. Alternatively, it is possible that KCNJ10
has a more important role in mouse kidneys than in human kidneys.28
In any case, our patients are probably in a state of compensated volume, whereas knockout mice are not.
The currently accepted model of renal epithelial salt transport posits that a favorable electrochemical gradient drives the influx of sodium (often transported with other substances) from the tubular lumen into the cell. This gradient is established by the basolateral sodium–potassium pump (Na+
-ATPase), which also provides an exit mechanism for sodium. In order for this primary active Na+
-ATPase to function, potassium must be able to leave the cell and must be readily available basolaterally.29
The task of KCNJ10
is to recycle potassium, which is necessary for the function of the primary active Na+
-ATPase. This “pump coupling” was postulated in 1958 by Koefoed-Johnsen and Ussing,30
and experimental evidence has been subsequently corroborated by many investigators.31,32
Our findings appear to constitute genetic proof for this basic physiological principle. A functional basolateral potassium channel also translates the potassium concentration gradient into a cell-negative transmembrane potential. Since uptake of luminal sodium chloride in the distal convoluted tubule is electroneutral, impairment of the negative membrane voltage itself would not be problematic. However, because the functions of other channels are critically dependent on membrane voltage, impairment of other transport processes (e.g., for chloride or magnesium) can occur.
activity, according to this view, provides a mechanism for indirectly regulating re-absorption of renal tubular sodium, which modulates volume homeostasis and maintains blood pressure. Indeed, our patients, lacking normal KCNJ10
activity, had low blood pressure. Moreover, chromosome 1q23.2, where the locus for KCNJ10
resides, has been implicated repeatedly as being linked to blood-pressure variation in different ethnic groups.33–35
In addition, a whole genome scan for the identification of blood-pressure modifiers (as a quantitative trait) in hypertensive and normotensive Lyon rat strains showed linkage to the region syntenic to human chromosome 1q23.2.36
Although the presence of basolateral potassium channels in the renal tubule, including the distal convoluted tubule, has long been known from electrophysiological studies, the molecular identity of these channels has remained unresolved.37
Our results should establish KCNJ10
as a critical component of basolateral potassium conductance in the distal convoluted tubule. Indeed, similarities in the electrophysiological properties of KCNJ10
and other known basolateral potassium channels have led to speculation that basolateral potassium conductance is achieved by the KCNJ10 protein in heteromerization with other potassium-channel proteins.38
Thus, loss of KCNJ10 function probably leads to a compensated state of salt loss, resulting in stimulation of the renin–angiotensin–aldosterone system and the respective renal tubular activation of potassium secretion in the aldosterone-sensitive nephron (collecting duct). The concomitant proximal tubular increase in bicarbonate (resulting in metabolic alkalosis) and calcium absorption (with consequent hypocalciuria) causes additional signs and symptoms of the EAST syndrome ( and ).
Seizures and ataxia develop in mice with Kcnj10
deletion, and they die shortly after birth, reflecting the critical role of KCNJ10
in the functioning of the central nervous system.16
Even mice with a conditional knockout of Kcnj10
in glial cells alone die at approximately 3 weeks of age.23
In humans, KCNJ10
is expressed in glial cells in the cerebral cortex and cerebellar cortex and in the caudate and putamen, and it is believed to establish the neuronal cell’s resting membrane potential through a process called potassium spatial buffering.39
With repeated excitation and repolarization, a neuron takes up substantial amounts of sodium and loses potassium. Thus, potassium accumulates extracellularly, decreasing the membrane potential, facilitating further excitations, and creating a diathesis toward seizures. Glial cells presumably take up the extruded potassium and distribute it through gap junctions; KCNJ10
has been implicated in this process.16
We propose that the absence of fully functional KCNJ10
removes this protective “potassium sink,” accounting for the seizures in our patients.
Investigations in mice have shown that Kcnj10
is expressed in intermediate cells in the stria vascularis and is required for the generation of the endocochlear potential, suggesting that it contributes indirectly to potassium enrichment of the endolymph.22
This explains why Kcnj10
knockout mice have markedly impaired hearing. Our patients’ hearing was only moderately impaired, and in two patients (1-3 and 1-4), hearing impairment was noted only on specific testing — findings that are consistent with the presence of residual channel function,
Our observations also show further genetic heterogeneity among the salt-losing tubulopathies and establish KCNJ10
as a basolateral potassium channel that is necessary for proper salt handling in the distal convoluted tubule of the kidney. These observations illustrate the critical role of KCNJ10
in the human brain and inner ear and provide the basis for further studies of the pathogenesis and potential treatment of epilepsy, movement disorders, and sensorineural deafness. Mutations in the transport genes of the renal tubular lumen often lead to kidney-specific phenotypes, as in the Gitelman syndrome and Bartter’s syndrome types I and II.2–4,40
Mutations in the basolateral subunit of a renal tubular chloride channel result in clinical findings in the kidney and the ear, as seen in Bartter’s syndrome type IV.6
We now know that mutations in KCNJ10
lead to distinct epithelial-transport abnormalities in the kidney and the ear. In other organs and systems, the KCNJ10
channel plays a major role in modulating resting membrane potentials in excitable cells, causing epilepsy if mutated.
The EAST syndrome should be suspected in patients presenting with any cardinal signs or symptoms of epilepsy, ataxia, or sensorineural deafness, especially if a concurrent electrolyte disorder, such as hypokalemia or hypomagnesemia, is diagnosed.
We speculate that the identification of the genetic basis of the EAST syndrome reveals a key role of KCNJ10 in the modification of volume homeostasis. Reevaluation of genomewide association studies may identify KCNJ10 as a candidate gene associated with blood pressure and its regulation.