4.5 Article

An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity

Journal

HUMAN MOLECULAR GENETICS
Volume 21, Issue 20, Pages 4497-4507

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds292

Keywords

-

Funding

  1. National Institutes of Health (National Institute of Child Health and Development) [HD26202]
  2. South Carolina Department of Disabilities and Special Needs (SCDDSN)
  3. Australian National Health and Medical Research Council [1008477]
  4. National Institutes of Health (National Institute of General Medical Sciences) [GM09392]

Ask authors/readers for more resources

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.303CG, 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 oleaky 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available