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1.
Proc Natl Acad Sci U S A ; 107(32): 14490-5, 2010 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-20651251

RESUMEN

Mutations of the KCNJ10 (Kir4.1) K(+) channel underlie autosomal recessive epilepsy, ataxia, sensorineural deafness, and (a salt-wasting) renal tubulopathy (EAST) syndrome. We investigated the localization of KCNJ10 and the homologous KCNJ16 in kidney and the functional consequences of KCNJ10 mutations found in our patients with EAST syndrome. Kcnj10 and Kcnj16 were found in the basolateral membrane of mouse distal convoluted tubules, connecting tubules, and cortical collecting ducts. In the human kidney, KCNJ10 staining was additionally observed in the basolateral membrane of the cortical thick ascending limb of Henle's loop. EM of distal tubular cells of a patient with EAST syndrome showed reduced basal infoldings in this nephron segment, which likely reflects the morphological consequences of the impaired salt reabsorption capacity. When expressed in CHO and HEK293 cells, the KCNJ10 mutations R65P, G77R, and R175Q caused a marked impairment of channel function. R199X showed complete loss of function. Single-channel analysis revealed a strongly reduced mean open time. Qualitatively similar results were obtained with coexpression of KCNJ10/KCNJ16, suggesting a dominance of KCNJ10 function in native renal KCNJ10/KCNJ16 heteromers. The decrease in the current of R65P and R175Q was mainly caused by a remarkable shift of pH sensitivity to the alkaline range. In summary, EAST mutations of KCNJ10 lead to impaired channel function and structural changes in distal convoluted tubules. Intriguingly, the metabolic alkalosis present in patients carrying the R65P mutation possibly improves residual function of KCNJ10, which shows higher activity at alkaline pH.


Asunto(s)
Anomalías Múltiples/genética , Mutación Missense , Canales de Potasio de Rectificación Interna/genética , Animales , Ataxia , Línea Celular , Epilepsia , Pérdida Auditiva Sensorineural , Humanos , Enfermedades Renales , Túbulos Renales Distales/patología , Ratones , Ratones Endogámicos C57BL , Canales de Potasio de Rectificación Interna/análisis , Síndrome , Transfección
2.
N Engl J Med ; 360(19): 1960-70, 2009 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-19420365

RESUMEN

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.


Asunto(s)
Ataxia/genética , Epilepsia/genética , Pérdida Auditiva Sensorineural/genética , Mutación Missense , Canales de Potasio de Rectificación Interna/genética , Defectos Congénitos del Transporte Tubular Renal/genética , Secuencia de Aminoácidos , Animales , Preescolar , Cromosomas Humanos Par 1 , Femenino , Genes Recesivos , Humanos , Escala de Lod , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Linaje , Fenotipo , Potasio/metabolismo , Análisis de Secuencia de ADN , Sodio/metabolismo , Síndrome
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