Molecular Basis of Decreased Kir4.1 Function in SeSAME/EAST Syndrome
- 1 December 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 21 (12), 2117-2129
- https://doi.org/10.1681/asn.2009121227
Abstract
SeSAME/EAST syndrome is a channelopathy consisting of a hypokalemic, hypomagnesemic, metabolic alkalosis associated with seizures, sensorineural deafness, ataxia, and developmental abnormalities. This disease links to autosomal recessive mutations in KCNJ10, which encodes the Kir4.1 potassium channel, but the functional consequences of these mutations are not well understood. In Xenopus oocytes, all of the disease-associated mutant channels (R65P, R65P/R199X, G77R, C140R, T164I, and A167V/R297C) had decreased K+ current (0 to 23% of wild-type levels). Immunofluorescence demonstrated decreased surface expression of G77R, C140R, and A167V expressed in HEK293 cells. When we coexpressed mutant and wild-type subunits to mimic the heterozygous state, R199X, C140R, and G77R currents decreased to 55, 40, and 20% of wild-type levels, respectively, suggesting that carriers of these mutations may present with an abnormal phenotype. Because Kir4.1 subunits can form heteromeric channels with Kir5.1, we coexpressed the aforementioned mutants with Kir5.1 and found that currents were reduced at least as much as observed when we expressed mutants alone. Reduction of pHi from approximately 7.4 to 6.8 significantly decreased currents of all mutants except R199X but did not affect wild-type channels. In conclusion, perturbed pH gating may underlie the loss of channel function for the disease-associated mutant Kir4.1 channels and may have important physiologic consequences.Keywords
This publication has 55 references indexed in Scilit:
- Variable loss of Kir4.1 channel function in SeSAME syndrome mutationsBiochemical and Biophysical Research Communications, 2010
- KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel functionProceedings of the National Academy of Sciences of the United States of America, 2010
- Mutations of KCNJ10 Together with Mutations of SLC26A4 Cause Digenic Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct SyndromeAmerican Journal of Human Genetics, 2009
- Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, andKCNJ10MutationsThe New England Journal of Medicine, 2009
- Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10Proceedings of the National Academy of Sciences of the United States of America, 2009
- An Inactivation Gate in the Selectivity Filter of KCNQ1 Potassium ChannelsBiophysical Journal, 2007
- Crystal structure of a Kir3.1-prokaryotic Kir channel chimeraThe EMBO Journal, 2007
- H Bonding at the Helix-Bundle Crossing Controls Gating in Kir Potassium ChannelsNeuron, 2007
- Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channelEMBO Reports, 2006
- CHARMM: A program for macromolecular energy, minimization, and dynamics calculationsJournal of Computational Chemistry, 1983