Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10

Abstract

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.Gitelman syndrome ͉ hypokalemia ͉ hypomagnesemia ͉ inwardly rectifying K ϩ channel ͉ renal salt wasting

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

“…The fact that all dogs had ataxia, but only some dogs had seizures, myokymia or neuromyotonia, is not surprising, as it is well known that potassium channel diseases can be phenotypically heterogeneous (variability of clinical signs and severity) in dogs 33 and humans. 1,2,43 The mildly delayed latencies of waves I and II, and the loss of waves III, IV and V, was repetitively found on the BAER tests of our affected dogs. This suggests a peripheral as well as central localisation for dysfunction within the auditory pathway.…”

“…44 This is a major difference in humans and mice, in which a cochlear dysfunction is assumed to be the origin of the hearing impairment. 1,2 The extent of hearing impairment in humans with KCNJ10 variation is variable and can sometimes be absent or only appreciated with specific testing. 45 None of the affected dogs showed any signs of clinically relevant hearing impairment.…”

“…1,2 It is caused by homozygous or compound heterozygous variations in the voltagegated potassium channel (VGKC), inwardly rectifying, subfamily J, member 10 gene (KCNJ10, alias KIR4.1; Gene/Locus MIM number 602208). Functional KCNJ10 subunits form homotetrameric or heterotetrameric (in coassembly with KCNJ16, alias KIR5.1) channels with two putative transmembrane regions.…”

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…Loss‐of‐function mutations in KCNJ10 cause SESAME syndrome ([MIM 612780], also called EAST syndrome), a disorder characterized by SNHL, electrolyte imbalance, seizures, ataxia and mental retardation. Here, the hearing loss is likely due to disrupted function of strial melanocytes (Scholl et al, 2009). KCNJ10 is also implicated in SNHL in autosomal recessive deafness‐4 (DFNB4) with enlarged vestibular aqueduct (EVA) [MIM 600791], and in autosomal recessive Pendred syndrome [MIM 274600].…”

Calcium-sensing Receptor Decreases Cell Surface Expression of the Inwardly Rectifying K+ Channel Kir4.1

“…The hypocalciuric, hypomagnesemic variant of Bartter syndrome, Gitelman syndrome, is due to loss of function mutations of the thiazide-sensitive NaCl co-transporter (6). The recently described SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) or EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy) syndrome is caused by loss of function mutations in Kir4.1 (KCNJ10), an inwardly rectifying K ϩ channel that is expressed in the basolateral membrane of the distal nephron (7)(8)(9)(10). Presumably, reduced activity of Kir4.1 impairs recycling of K ϩ for the Na,K-ATPase reducing net transepithelial Na 2ϩ transport.…”