An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.
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 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.
JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.
Kyoko
K
Takano
Dan
D
Liu
Patrick
P
Tarpey
Esther
E
Gallant
Alex
A
Lam
Shawn
S
Witham
Emil
E
Alexov
Alka
A
Chaubey
Roger E
RE
Stevenson
Charles E
CE
Schwartz
Philip G
PG
Board
Angela F
AF
Dulhunty
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications / Q000235:genetics*; D053447:Channelopathies / Q000150:complications / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism; D005190:Family; D040181:Genetic Diseases, X-Linked / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism
C108828:CLIC2 protein, human; D018118:Chloride Channels; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium