Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations
Detlef B et al. – Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Findings show that the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney, plays a major role in renal salt handling and thus possibly in blood-pressure maintenance and its regulation as well. Methods- Study of the genetic basis of EAST syndrome (an autosomal recessive disease): presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy
- Subjects: 5 children from 2 consanguineous families with epilepsy in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis
- Whole-genome linkage analysis in 4 affected children in 1 family
- Evaluation of newly identified mutations in a potassium-channel gene by use of a heterologous expression system
- Assessment of protein expression and function in genetically modified mice
- Sequencing of the candidate gene
Results- Linkage analysis identified a single significant locus on chromosome 1q23.2 with lod score of 4.98
- This region contained the KCNJ10 gene
- Gene sequencing showed 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
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