KCNQ2 encephalopathy typically presents with tonic seizures from the first week of life. The seizures can be frequent and often difficult to treat. Seizures can resolve within months or years but can impair the development of several domains such as motor, social, cognitive and language. [1]
Pathogenic variations in KCNQ2 are associated with developmental and epileptic encephalopathy (DEE). KCNQ2 is a voltage gated potassium channel within the brain, located on the long arm of chromosome 20, at position 13.3 (20p13.3). KCNQ2 gene is a critical molecular component of the M-current, a subthreshold voltage-gated potassium current controlling neuronal excitability by dampening repetitive action potential firing. DEE is caused by loss of function mutations in the KCNQ2 gene thereby reducing the activation threshold of the neuron and increasing the risk of hyperexcitability. KCNQ2 belongs to a family of ion channels, abbreviated Kv7.2. The KCNQ gene subfamily consists of five members (KCNQ1–5), all encoding voltage-gated potassium (K+) channel subunits (Kv7.1–5). The Kv7.1 subunit is expressed in the heart and Kv7.2-5 subunits are most abundantly expressed in the nervous system. [2]
KCNQ2 channels are voltage-dependent K+ currents which represent the molecular basis of the M-current (a voltage-gated and K+-selective current which derives its name from its suppression upon activation of M1 muscarinic receptors).
KCNQ2 encephalopathy is caused by heterozygous missense or in-frame indel mutations shown to have a dominant negative (DN; >50% reduction of the M-current density), or gain of function effect (GOF; >100% of the M-current density) when co-expressed with wild-type subunits. [3]
KCNQ2 is ultimately diagnosed by molecular genetic testing. Approaches include the use of a multigene panel that includes the KCNQ2 gene and other genes of interest, comprehensive genomic testing, or a single-gene test for pathogenic variants of the KCNQ2 gene. [4]
Anticonvulsant drugs can be efficacious at reducing seizure frequency and severity. Alternate treatments such as specialized diets, surgery and devices can be investigated if medications are unable to control the seizures. [5]
Knockout and knock in mouse models have been generated to study the role of Kv7.2 channels in vivo. Both these mouse models show a reduced seizure threshold. [6]
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.
BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.
Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among other tissues. In the cardiac cells, Kv7.1 mediates the IKs (or slow delayed rectifying K+) current that contributes to the repolarization of the cell, terminating the cardiac action potential and thereby the heart's contraction. It is a member of the KCNQ family of potassium channels.
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.
Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.
Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.
Benign familial neonatal seizures (BFNS), also referred to as benign familial neonatal epilepsy (BFNE), is a rare autosomal dominant inherited form of seizures. This condition manifests in newborns as brief and frequent episodes of tonic-clonic seizures with asymptomatic periods in between. Characteristically, seizure activity spontaneously ends during infancy and does not affect childhood development. However, some studies have reported that a minority of children with BFNS consequently develop intellectual disability. Additionally, BFNS increases lifetime susceptibility to seizures as approximately 14% of those afflicted go on to develop epilepsy later in life. There are three known genetic causes of BFNE, two being the voltage-gated potassium channels KCNQ2 (BFNC1) and KCNQ3 (BFNC2) and the third being a chromosomal inversion (BFNC3). There is no obvious correlation between most of the known mutations and clinical variability seen in BFNE.
Kv7.2 (KvLQT2) is a voltage- and lipid-gated potassium channel protein coded for by the gene KCNQ2.
Kv7.3 (KvLQT3) is a potassium channel protein coded for by the gene KCNQ3.
Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4 micromolar disinhibiting acetylcholine release, and increasing hippocampal CA3-schaffer collateral mediated glutamate release onto CA1 pyramidal neurons. In a murine model linopirdine is able to nearly completely reverse the senescence-related decline in cortical c-FOS, an effect which is blocked by atropine and MK-801, suggesting Linopirdine can compensate for the age related decline in acetylcholine release. Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3. Linopirdine also acts as a glycine receptor antagonist in concentrations typical for Kv7 studies in the brain.
Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2(MiRP2) is a protein that in humans is encoded by the KCNE3 gene.
Potassium voltage-gated channel subfamily KQT member 4, also known as voltage-gated potassium channel subunit Kv7.4, is a protein that in humans is encoded by the KCNQ4 gene.
Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.
Potassium voltage-gated channel subfamily S member 3 (Kv9.3) is a protein that in humans is encoded by the KCNS3 gene. KCNS3 gene belongs to the S subfamily of the potassium channel family. It is highly expressed in pulmonary artery myocytes, placenta, and parvalbumin-containing GABA neurons in brain cortex. In humans, single-nucleotide polymorphisms of the KCNS3 gene are associated with airway hyperresponsiveness, whereas decreased KCNS3 mRNA expression is found in the prefrontal cortex of patients with schizophrenia.
Potassium voltage-gated channel subfamily A member 7 also known as Kv1.7 is a protein that in humans is encoded by the KCNA7 gene. The protein encoded by this gene is a voltage-gated potassium channel subunit. It may contribute to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.
KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.
Retigabine (INN) or ezogabine (USAN) is an anticonvulsant used as an adjunctive treatment for partial epilepsies in treatment-experienced adult patients. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011. Production was discontinued in June 2017.
M current is a type of noninactivating potassium current first discovered in bullfrog sympathetic ganglion cells.
KCNQ genes encode family members of the Kv7 potassium channel family. These include Kv7.1 (KCNQ1) - KvLQT1, Kv7.2 (KCNQ2), Kv7.3 (KCNQ3), Kv7.4 (KCNQ4), and Kv7.5 (KCNQ5). Four of these (KCNQ2-5) are expressed in the nervous system. They constitute a group of low-threshold voltage-gated K+ channels originally termed the ‘M-channel’ (see M-current). The M-channel name comes from the classically described mechanism wherein the activation of the muscarinic acetylcholine receptor deactivated this channel.
XEN1101 (encukalner) is an experimental small molecule anticonvulsant and selective Kv7.2/Kv7.3 potassium channel opener being investigated as a treatment for refractory focal onset seizures and major depressive disorder.
 | This genetic disorder article is a stub. You can help Wikipedia by expanding it. |
