About KCNQ2/3: An Introduction
What is KCNQ2? What is KCNQ3?
KCNQ2 and KCNQ3 (or KCNQ2/3) are genes encoding a brain signaling molecule called a potassium ion channel. KCNQ2/3 channels are buried in the exterior surface membrane of brain cells. Nearly all brain signaling cells, or neurons, have KCNQ2/3 channels. When these channels open, potassium ions flow across the membrane. The main normal role of KCNQ2/3 ion flow is to act as a brake, delaying, slowing, and limiting the electrical signaling of these neurons.
What is meant by a KCNQ2 or KCNQ3 "variant" or "mutation"?
Each KCNQ2 or KCNQ3 gene is a sequential listing of about 75,000 coded molecules (called bases). The bases are A, C, T, or G. Each gene's base sequence is a recipe that gives specific instructions for construction of the KCNQ2 channel. Simply, a person has a KCNQ2 variant if the listing of bases in their KCNQ2 gene is different than in most people. It is important to note that many such variants have no disease effects. However, variants that change the "recipe" and prevent KCNQ2/3 channels from properly carrying ions across the membrane can lead to illness.
Why do some KCNQ2/3 variants cause illness?
Evidence supports the idea that most KCNQ2/3 variants causing disease reduce the activity of the KCNQ2/3 containing channels in neurons. Such loss of ion carrying capacity makes the nerve cells too active, and drives abnormal electrical firing patterns in the brain's cellular networks.
What is the evidence?
Scientists can measure the opening and closing of KCNQ2/3 channel very accurately using laboratory experiments. They have found that many patients' variants reduce openings. Fewer number of openings means less channel function.
Some KCNQ2 variants have been introduced into mice and used to model the human illnesses. Although mouse brains are (of course) different from human brains, the mice with KCNQ2/3 variants nonetheless show predicted effects. Cells showed reduced KCNQ2/3 channel opening, and the mice showed increased seizure tendencies as measured by their behavior and brain wave signals (electroencephalogram).
Although brain KCNQ2/3 channel activity has not been measured directly in humans, electroencephalograms from babies and children with KCNQ2/3 variants show clear signs that cells are firing excessively, consistent with the channel and mouse results observed in labs.
This evidence is incomplete and more needs to be gathered.
Why do variants in KCNQ2 or KCNQ3 cause epilepsy that usually begins in the first days of life?
We know that KCNQ2 and KCNQ3 are two of about 400 human genes for different ion channels. Why so many? One reason is analogous to clothing. Infants, children, teens and adults change the types of clothes they wear as they mature. Similarly, different subsets of our ion channels are particularly important at different ages. Although KCNQ2/3 channels are present in brain cells throughout life, it seems that their calming roles are uniquely critical during the first days and months of life.
Again, more evidence about this needs to be gathered.
Why do the known variants in KCNQ2 or KCNQ3 cause symptoms that differ in severity and duration?
This is a very important question current research is attempting to answer. Knowing the answer will help direct future efforts to develop treatments for more severe cases of KCNQ2/3 related illness. The current view is that the severity of illness is usually related to the degree of functional deficiency resulting from the KCNQ2/3 variant.
Variants in people who have seizures as newborn babies but go on to experience a good developmental outcome have often been found to reduce channel activity very partially. Motor, language, and social skills may be unaffected by such variants, even though neonatal seizures may be very frequent. Children of such individuals have a 50% risk of acquiring the KCNQ2 variant. This syndrome is called benign familial neonatal epilepsy (or, synonymously, benign familial neonatal convulsions or seizures).
In some other patients, neonatal seizures may persist despite medication and be accompanied by moderate to profound slowing of development. Varients from such children have only recently begun to be studied, but some have been shown to reduce channel activity almost totally.
This idea does not explain all cases. In some variants from severely affected patients, lab testing has shown no reason for the severe effects. Also, in a small number of KCNQ2/3 variants, some lab tests actually show an increase in ion flows. Current research is studying such variants more, to learn if different treatments are needed compared to the more common situation where channel activity is reduced.
Genetics Home Reference is the National Library of Medicine's web site for consumer information about genetic conditions. KCNQ2 KCNQ3 Benign Familial Neonatal Epilepsy
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Last Updated: 12/15/2015