title: KCNJ10 mutations disrupt function in patients with EAST syndrome.
abstract: OBJECTIVE
  Mutations in the inwardly-rectifying K+ channel KCNJ10/Kir4.1 cause an autosomal recessive disorder characterized by epilepsy, ataxia, sensorineural deafness and tubulopathy (EAST syndrome). KCNJ10 is expressed in the kidney distal convoluted tubule, cochlear stria vascularis and brain glial cells. Patients clinically diagnosed with EAST syndrome were genotyped to identify and study mutations in KCNJ10.
  
  
  METHODS
  Patient DNA was sequenced and new mutations identified. Mutant and wild-type KCNJ10 constructs were cloned and heterologously expressed in Xenopus oocytes. Whole-cell K+ currents were measured by two-electrode voltage clamping.
  
  
  RESULTS
  Three new mutations in KCNJ10 (p.R65C, p.F75L and p.V259fs259X) were identified, and mutation p.R297C, previously only seen in a compound heterozygous patient, was found in a homozygous state. Wild-type human KCNJ10-expressing oocytes showed strongly inwardly-rectified currents, which by comparison were significantly reduced in all the mutants (p < 0.001). Specific inhibition of KCNJ10 currents by Ba2+ demonstrated residual function in all mutant channels (p < 0.05) but V259X.
  
  
  CONCLUSIONS
  This study confirms that EAST syndrome can be caused by many different mutations in KCNJ10 that significantly reduce K+ conductance. EAST syndrome should be considered in any patient with a renal Gitelman-like phenotype with additional neurological signs and symptoms like ataxia, epilepsy or sensorineural deafness.
authors.affiliation: Centre for Nephrology, University College London, Royal Free Hospital, London, UK.
authors.forename: Bernard
authors.initials: B
authors.lastname: Freudenthal
authors.forename: Duvaraka
authors.initials: D
authors.lastname: Kulaveerasingam
authors.forename: Lokesh
authors.initials: L
authors.lastname: Lingappa
authors.forename: Mehul A
authors.initials: MA
authors.lastname: Shah
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.forename: Milos
authors.initials: M
authors.lastname: Ognjanovic
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dorison
authors.forename: Markus
authors.initials: M
authors.lastname: Reichold
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Anselm A
authors.initials: AA
authors.lastname: Zdebik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005260:Female; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D007686:Kidney Tubules, Distal / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D017422:Sequence Analysis, DNA; D014982:Xenopus laevis / Q000235:genetics / Q000502:physiology; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying