Channelopathy

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.

Causes

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

Types

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 typeCACNA1C-related disordersVoltage-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 orVoltage-dependent calcium channel (calciumopathy)KCNH1-related disordersVoltage-gated potassium channel, KCNH1KCNT1-related epilepsyVoltage-gated potassium channel, KCNT1 Lambert–Eaton myasthenic syndrome Voltage-gated calcium channel Long QT syndromemain 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 channelsSCN2A-related disordersVoltage-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.

Channelopathy

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