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An X-linked Channelopathy with Cardiomegaly due to a CLIC2 Mutation Enhancing Ryanodine Receptor Channel Activity

Takano, Kyoko; Liu, Dan; Tarpey, Patrick; Gallant, Esther; Lam, Alex; Witham, Shawn; Alexov, Emil; Chaubey, Alka; Stevenson, Roger E; Schwartz, Charles E; Board, Philip; Dulhunty, Angela

Description

Chloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca. 2+ release channels. These RyR proteins play a major role in the regulation of Ca. 2+ signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X-linked intellectual...[Show more]

dc.contributor.authorTakano, Kyoko
dc.contributor.authorLiu, Dan
dc.contributor.authorTarpey, Patrick
dc.contributor.authorGallant, Esther
dc.contributor.authorLam, Alex
dc.contributor.authorWitham, Shawn
dc.contributor.authorAlexov, Emil
dc.contributor.authorChaubey, Alka
dc.contributor.authorStevenson, Roger E
dc.contributor.authorSchwartz, Charles E
dc.contributor.authorBoard, Philip
dc.contributor.authorDulhunty, Angela
dc.date.accessioned2015-12-10T22:29:20Z
dc.identifier.issn0964-6906
dc.identifier.urihttp://hdl.handle.net/1885/54857
dc.description.abstractChloride intracellular channel 2 (CLIC2) protein is a member of the glutathione transferase class of proteins. Its' only known function is the regulation of ryanodine receptor (RyR) intracellular Ca. 2+ release channels. These RyR proteins play a major role in the regulation of Ca. 2+ signaling in many cells. Utilizing exome capture and deep sequencing of genes on the X-chromosome, we have identified a mutation in CLIC2 (c.303C>G, p.H101Q) which is associated with X-linked intellectual disability (ID), atrial fibrillation, cardiomegaly, congestive heart failure (CHF), some somatic features and seizures. Functional studies of the H101Q variant indicated that it stimulated rather than inhibited the action of RyR channels, with channels remaining open for longer times and potentially amplifying Ca. 2+ signals dependent on RyR channel activity. The overly active RyRs in cardiac and skeletal muscle cells and neuronal cells would result in abnormal cardiac function and trigger post-synaptic pathways and neurotransmitter release. The presence of both cardiomegaly and CHF in the two affected males and atrial fibrillation in one are consistent with abnormal RyR2 channel function. Since the dysfunction of RyR2 channels in the brain via 'leaky mutations' can result in mild developmental delay and seizures, our data also suggest a vital role for the CLIC2 protein in maintaining normal cognitive function via its interaction with RyRs in the brain. Therefore, our patients appear to suffer from a new channelopathy comprised of ID, seizures and cardiac problems because of enhanced Ca. 2+ release through RyRs in neuronal cells and cardiac muscle cells.
dc.publisherOxford University Press
dc.sourceHuman Molecular Genetics
dc.subjectKeywords: ion channel; ryanodine receptor; ryanodine receptor 2; article; calcium signaling; calcium transport; cardiomegaly; channelopathy; chloride intracellular channel 2 gene; chromosome analysis; cognition; congestive heart failure; exome; follow up; gene; gen
dc.titleAn X-linked Channelopathy with Cardiomegaly due to a CLIC2 Mutation Enhancing Ryanodine Receptor Channel Activity
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume21
dc.date.issued2012
local.identifier.absfor110311 - Medical Genetics (excl. Cancer Genetics)
local.identifier.ariespublicationu4020362xPUB312
local.type.statusPublished Version
local.contributor.affiliationTakano, Kyoko, Kanagawa Children's Medical Center
local.contributor.affiliationLiu, Dan, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationTarpey, Patrick, Wellcome Trust Sanger Institute
local.contributor.affiliationGallant, Esther, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLam, Alex, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationWitham, Shawn, Clemson University
local.contributor.affiliationAlexov, Emil, Clemson University
local.contributor.affiliationChaubey, Alka, Greenwood Genetic Center
local.contributor.affiliationStevenson, Roger E, Greenwood Genetic Center
local.contributor.affiliationSchwartz, Charles E, Greenwood Genetic Center
local.contributor.affiliationBoard, Philip, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDulhunty, Angela, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue20
local.bibliographicCitation.startpage4497
local.bibliographicCitation.lastpage4507
local.identifier.doi10.1093/hmg/dds292
dc.date.updated2016-02-24T10:27:51Z
local.identifier.scopusID2-s2.0-84867115345
local.identifier.thomsonID000309460300011
CollectionsANU Research Publications

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