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, 360 (19), 1960-70

Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations


Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations

Detlef Bockenhauer et al. N Engl J Med.


Background: Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy).

Methods: Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice.

Results: Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting.

Conclusions: Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.

Conflict of interest statement

Dr. Sheridan reports receiving grant support from the Well-being of Women. No other potential conflict of interest relevant to this article was reported.


Figure 1
Figure 1. Pedigrees of Family 1 and Family 2 and Clinical Findings in Patient 1-1
The pedigree of Family 1 (Panel A) shows four affected members, and that of Family 2 one affected member. Squares indicate male family members and circles female family members; filled squares and circles indicate that the patients are affected. Double lines between parents indicate that the parents are related. An MRI scan of the brain obtained from Patient 1-1 at 9 years of age (Panel B) shows normal cerebral and cerebellar structures. An audiogram of the left ear in the same patient at 14 years of age (Panel C) shows moderate hearing loss, which is more pronounced at higher frequencies. A hearing deficit of up to 20 dB is considered normal for frequencies from 250 to 8000 Hz.
Figure 2
Figure 2. Linkage Studies
A haplotype reconstruction (Panel A) for the locus on chromosome 1 shows identical alleles (indicated by the same color) in the linked region in all affected patients. The numbers (i.e., 1 or 2) next to the alleles indicate the respective status of the single-nucleotide polymorphisms used for genotyping. Recombinations in Patients 1-1 and 1-2 define this region. The parametric multipoint linkage analysis of the whole genome for Family 1 (Panel B) has a single significant peak, with a maximum lod score of almost 5 on chromosome 1. Genetic distance (in centimorgans) and individual chromosomes (1 to 22) are indicated on the lower and upper x axes, respectively.
Figure 3
Figure 3. Sequence Analysis and Functional Studies
Panel A shows sequence chromatograms for a wild-type (WT) control and Patient 1-1. The homozygous missense mutation c.194G C (CGC CCC; p.R65P) is present in the patient’s chromatogram (arrow). Panel B shows sequence chromatograms for a wild-type control and Patient 2-1. The homozygous missense mutation c.229 G C (GGC CGC; p.G77R) is present in the patient’s chromatogram (arrow). Panel C shows a protein-alignment (homology) plot of the first transmembrane region of KCNJ10 in 21 vertebrate species, with complete conservation of R65 and G77 (arrows). A model based on the crystal structure of a bacterial homologue of KCNJ10, (i.e., kcsa), in Panel D, shows the localization of mutations within the first transmembrane region. When heterologous expression of wild-type KNCJ10 and mutants (R65P and G77R) in xenopus oocytes was measured with the use of a two-electrode voltage clamp, a significant decrease of specific currents in mutant KCNJ10 was observed, as shown in Panel E. N denotes the number of experiments.
Figure 4
Figure 4. Kcnj10 in Mice
Serial sections of a kidney from a wild-type mouse (Panel A), stained for antibodies to the proteins NKCC2 (green, indicating luminal thick ascending limb), KCNJ10 (green), NCC (green, indicating luminal distal convoluted tubule), AQP2 (red, indicating principal cells of the luminal collecting duct), and calbindin (blue, indicating distal convoluted tubule and collecting duct) show staining for KCNJ10 basolaterally in the distal part of the nephron only. The glomerulus is indicated by an asterisk. Scale bars indicate 100 μm. Growth curves for wild-type mice, heterozygous (HE) mice, and homozygous (knockout) mice (based on the mean values for two animals of each type) show virtually no growth of the knockout mice (Panel B), which died after day 8. The photograph of two 6-day-old mice from the same litter, one knockout and one wild-type, shows the growth arrest in the knockout mouse. The bar graph (Panel C) shows the mean results of urinalysis for 7 knockout mice as compared with 29 wild-type and heterozygous mice, all at the age of 3 days. Significant results were obtained for creatinine concentration (Creat) (a decrease), sodium excretion (Na/Creat) (an increase), indicating renal salt wasting, and calcium excretion (Ca/Creat) (a decrease) in the knockout mice.

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