Channelopathy
Diseases caused by dysfunction of ion channels or related proteins
Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes.
Channels are typically formed as complexes of several individual, often identical or homologous, proteins. Depending on the type and location of the mutation, it may lead to (partial) loss of function, affect gating, conductance, ion selectivity, or signal transduction of the channel. Gain of function variants in channels are also associated with several diseases, and a key target for knockdown genetic therapies.
Channelopathies can be categorized based on the organ system which they are associated with. In the cardiovascular system, the electrical impulse needed for each heartbeat is made possible by the electrochemical gradient of each heart cell. Because the heartbeat is dependent on the proper movement of ions across the surface membrane, cardiac channelopathies make up a key group of heart diseases. Long QT syndrome, the most common form of cardiac channelopathy, is characterized by prolonged ventricular repolarization, predisposing to a high risk of ventricular tachyarrhythmias (e.g., torsade de pointes), syncope, and sudden cardiac death.
The channelopathies of human skeletal muscle include hyper- and hypokalemic (high and low potassium blood concentrations) periodic paralysis, myotonia congenita and paramyotonia congenita.
Channelopathies affecting synaptic function are a type of synaptopathy.
01Causes
Genetic
Mutations in genes encoding ion channels, which cause defects in channel function, are the most common cause of channelopathies. Non-coding changes can also result in channelopathy. Changes in the promoter region, binding site of transcription factors and at splice sites are known to be causative for several epilepsies.
Acquired
Channelopathies can develop due to:
- Autoantibodies, like in anti-NMDA receptor encephalitis
- Transcriptional regulation, for example in response to drugs or traumatic brain injury
- Post-transcriptional regulation
- Genetic predisposition in combination with environmental factors
02Types
The types in the following table are commonly accepted. Channelopathies currently under research, like Kir4.1 potassium channel in multiple sclerosis, are not included.
| Condition | Channel type |
|---|---|
| Bartter syndrome | various, by type |
| Brugada syndrome | various, by type |
| CACNA1C-related disorders | Voltage-gated calcium channel |
| Catecholaminergic polymorphic ventricular tachycardia (CPVT) | Ryanodine receptor |
| Congenital hyperinsulinism | Inward-rectifier potassium ion channel |
| Cystic fibrosis | Chloride channel, CFTR |
| Dravet syndrome | Voltage-gated sodium channel |
| Epilepsy | various, including: sodium, potassium, calcium, chloride channels, GABAA receptors, ionotropic glutamate receptors, nicotinic acetylcholine receptors and hyperpolarization-activated cyclic nucleotide-gated channels |
| Episodic ataxia | Voltage-gated potassium channel |
| Erythromelalgia | Voltage-gated sodium channel |
| Generalized epilepsy with febrile seizures plus | Voltage-gated sodium channel |
| Familial hemiplegic migraine | various |
| Associated with one particular disabling form of fibromyalgia | Voltage-gated sodium channel |
| Hyperkalemic periodic paralysis | Voltage-gated sodium channel |
| Hypokalemic periodic paralysis | Voltage-gated sodium channel or Voltage-dependent calcium channel (calciumopathy) |
| KCNH1-related disorders | Voltage-gated potassium channel, KCNH1 |
| KCNT1-related epilepsy | Voltage-gated potassium channel, KCNT1 |
| Lambert-Eaton myasthenic syndrome | Voltage-gated calcium channel |
| Long QT syndrome main type Romano-Ward syndrome |
various, by type |
| Malignant hyperthermia | Ligand-gated calcium channel |
| Mucolipidosis type IV | Non-selective cation channel |
| Myotonia congenita | Voltage-dependent chloride channel |
| Neuromyelitis optica | Aquaporin-4 water channel |
| Neuromyotonia | Voltage-gated potassium channel |
| Nonsyndromic deafness | various |
| Paramyotonia congenita (a periodic paralysis) |
Voltage-gated sodium channel |
| Polymicrogyria (brain malformation) | Voltage-gated sodium channel, SCN3A ATP1A3 |
| Retinitis pigmentosa (some forms) | Ligand-gated non-specific ion channels |
| SCN2A-related disorders | Voltage-gated sodium channel, SCN2A |
| Short QT syndrome | various potassium channels suspected |
| Temple-Baraitser syndrome | Voltage-gated potassium channel, KCNH1 |
| Timothy syndrome | Voltage-dependent calcium channel |
| Tinnitus | Voltage-gated potassium channel of the KCNQ family |
| Seizure | Voltage-dependent potassium channel |
| Zimmermann-Laband syndrome, type1 | Voltage-gated potassium channel, KCNH1 |
Ion channels versus ion pumps
Both channels and pumps are ion transporters which move ions across membranes. Channels move ions quickly, through passive transport, down electrical and concentration gradients (moving "downhilll"); whereas pumps move ions slowly, through active transport, building-up gradients (moving "uphill"). Historically the difference between the two seemed cut and dried; however, recent research has shown that in some ion transporters, it is not always clear whether it functions as a channel or a pump.
Diseases involving ion pumps can produce symptoms similar to channelopathies, as they both involve the movement of ions across membranes. Brody disease (also known as Brody myopathy) includes symptoms similar to myotonia congenita, including muscle stiffness and cramping after initiating exercise (delayed muscle relaxation). However, it is pseudo-myotonia as those with Brody disease have normal EMG.
Due to similar symptoms, different genes for both channels and pumps can be associated with the same disease. For instance, polymicrogyria has been associated with the channel gene SCN3A and the pump gene ATP1A3, among other genes that are not ion transporters.
Sources and credits
This article is adapted from the Wikipedia article “Channelopathy”, written by its contributors and licensed under CC BY-SA 4.0. Fathomly has changed the layout, removed citation markers, navigation and maintenance notices, and adjusted punctuation. This adapted version is shared under the same license. For references, see the original article.
Images, from Wikimedia Commons:
- Ion channel image - Kim 2014 PMCID 3935107.png by June-Bum Kim, CC BY-SA 3.0
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