Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.2-23.3. Direct DNA sequencing of KCNJ10, which encodes an inwardly rectifying K(+) channel, identifies previously unidentified missense or nonsense mutations on both alleles in all affected subjects. These mutations alter highly conserved amino acids and are absent among control chromosomes. Many of these mutations have been shown to cause loss of function in related K(+) channels. These findings demonstrate that loss-of-function mutations in KCNJ10 cause this syndrome, which we name SeSAME. KCNJ10 is expressed in glia in the brain and spinal cord, where it is believed to take up K(+) released by neuronal repolarization, in cochlea, where it is involved in the generation of endolymph, and on the basolateral membrane in the distal nephron. We propose that KCNJ10 is required in the kidney for normal salt reabsorption in the distal convoluted tubule because of the need for K(+) recycling across the basolateral membrane to enable normal activity of the Na(+)-K(+)-ATPase; loss of this function accounts for the observed electrolyte defects. Mice deficient for KCNJ10 show a related phenotype with seizures, ataxia, and hearing loss, further supporting KCNJ10's role in this syndrome. These findings define a unique human syndrome, and establish the essential role of basolateral K(+) channels in renal electrolyte homeostasis.
Scholl
Ute I
UI
Department of Genetics, The Howard Hughes Medical Institute, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Choi
Murim
M
Liu
Tiewen
T
Ramaekers
Vincent T
VT
Häusler
Martin G
MG
Grimmer
Joanne
J
Tobe
Sheldon W
SW
Farhi
Anita
A
Nelson-Williams
Carol
C
Lifton
Richard P
RP
D000015:Abnormalities, Multiple / Q000209:etiology / Q000235:genetics*; D000818:Animals; D001259:Ataxia; D002878:Chromosomes, Human, Pair 1; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D012640:Seizures / Q000235:genetics; D013577:Syndrome; D014018:Tissue Distribution; D014882:Water-Electrolyte Balance / Q000235:genetics; D000098854:Kcnj10 Channel
D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying