Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.
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.
Great Ormond Street Hospital-University College London, London, United Kingdom.
Detlef
D
Bockenhauer
Sally
S
Feather
Horia C
HC
Stanescu
Sascha
S
Bandulik
Anselm A
AA
Zdebik
Markus
M
Reichold
Jonathan
J
Tobin
Evelyn
E
Lieberer
Christina
C
Sterner
Guida
G
Landoure
Ruchi
R
Arora
Tony
T
Sirimanna
Dorothy
D
Thompson
J Helen
JH
Cross
William
W
van't Hoff
Omar
O
Al Masri
Kjell
K
Tullus
Stella
S
Yeung
Yair
Y
Anikster
Enriko
E
Klootwijk
Mike
M
Hubank
Michael J
MJ
Dillon
Dirk
D
Heitzmann
Mauricio
M
Arcos-Burgos
Mark A
MA
Knepper
Angus
A
Dobbie
William A
WA
Gahl
Richard
R
Warth
Eamonn
E
Sheridan
Robert
R
Kleta
D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D015499:Renal Tubular Transport, Inborn Errors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012964:Sodium / Q000378:metabolism; D013577:Syndrome; D000098854:Kcnj10 Channel
D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D012964:Sodium; D011188:Potassium