ArticleHuman molecular genetics2012
An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
63 citing papers in PubMed, 94 citations in OpenAlex.
- Electrostatics and disease: Large-scale assessment of human missense variants causing protein charge alterations and their implications for disease.Biophysical journal · 2026Article
- X-Linked Muscular Dystrophy in a Cat with a Putative Variant in theAnimals : an open access journal from MDPI · 2026Article
- Prenatal diagnosis of distal Xq28 duplication syndrome: case reports and literature review.Molecular cytogenetics · 2026Article
- Article
- Heart on Fire: UnmaskingMethodist DeBakey cardiovascular journal · 2025Article
- Review
- Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases.Journal of human genetics · 2024Article
- Most Monogenic Disorders Are Caused by Mutations Altering Protein Folding Free Energy.International journal of molecular sciences · 2024Article
- The RyR1 P3528S Substitution Alters Mouse Skeletal Muscle Contractile Properties and RyR1 Ion Channel Gating.International journal of molecular sciences · 2023Article
- Unraveling the Multifaceted Role of the Golgi Apparatus: Insights into Neuronal Plasticity, Development, Neurogenesis, Alzheimer's Disease, and SARS-CoV-2 Interactions.Brain sciences · 2023Review
- Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome.Human genetics · 2023Article
- On the linkage of thermodynamics and pathogenicity.Current opinion in structural biology · 2023Review
- Increased level of RAB39B leads to neuronal dysfunction and behavioural changes in mice.Journal of cellular and molecular medicine · 2023Article
- Assessing Variants of Uncertain Significance Implicated in Hearing Loss Using a Comprehensive Deafness Proteome.Research square · 2023Article
- Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 (Frontiers in molecular neuroscience · 2023Article
- Post-translational modifications and protein quality control of mitochondrial channels and transporters.Frontiers in cell and developmental biology · 2023Review
- An In silico Approach towards Finding the Cancer-Causing Mutations in Human MET Gene.International journal of genomics · 2023Article
- Review
- Electrostatics in Computational Biophysics and Its Implications for Disease Effects.International journal of molecular sciences · 2022Review
- Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene.Genetics research · 2022Article
3 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.