By: Sofia Arreguin
KCNQ3 Genetic Mutation and Epilepsy
What is KCNQ3?
Known by other names, such as BFNC2, KV7.3, or EBN2, KCNQ3 is a gene responsible for encoding a protein that works to regulate neuronal excitability. The KCNQ3 protein, known as Kv7.3, provides instructions for the production of potassium (K+) channels within the cell membrane of a neuron, and it is through these channels that potassium ions are able to flow into and out of the cell (“Unlocking the Secrets of KCNQ3,” n.d.). This displays the role KCNQ3 also has in allowing neuronal communication within the brain. Normally, when a neuron communicates with, or stimulates, another neuron, an action potential, or electrically charged signal, is released. Once it flows through the axon and dendrites and reaches the terminal buttons, its force allows the neuron to release neurotransmitters into the receiving cell, or postsynaptic neuron, across the synapse. This release of neurotransmitters is essentially the manner in which a neuron communicates with another neuron in a cell. Once this occurs, the potassium channels, created by the KCNQ3 gene, send a signal known as the M-current, which stops the neuron from communicating another signal to a receiving neuron (National Library of Medicine, 2011). In doing so, the channel ensures that the neuron is not constantly firing or active, effectively opposing the presence of a neuron with excess excitability; this excess excitability is a known factor in causing seizures.
KCNQ3-Related Epilepsy
However, mutations or variants within this gene, specifically on chromosome 8, can produce seizures (“Families,” 2023). Such incidents can be seen in four types of KCNQ3-related disorders: Benign Familial Neonatal Seizures, Self-Limited Familial Neonatal Epilepsy (SLFNE), Self-Limited Familial Infantile Epilepsy (SLFIE), and Neurodevelopmental Disorder (DD). For instance, benign familial neonatal seizures result from a mutation within the KCNQ3 gene, which can allow for repetitive seizures in infants (National Library of Medicine, 2011). Changes occur within the amino acids, or building blocks, of a protein; specifically, the KCNQ3 protein. As a result of the mutation, the protein is unable to efficiently provide instructions for the formation of a potassium channel or produce the M-current signal. When there is a weakened M-current, there is reduced power in inhibiting a neuron from firing continuously, leading to increased firing, or excitability, and the manifestation of seizures. Similarly, mutations in the KCNQ3 protein, and the resulting hyperexcitability that follows from a weakened M-current, produce SLFNE and SLFIE. The KCNQ3-SLFNE disorder usually manifests during the 2nd or 8th day of a newborn’s life, and lasts for 1 year, consisting of seizures that often persist for 1-2 minutes (Miceli et al., 2023). Seizure types include tonic and focal clonic seizures; tonic seizures include stiffening of the limbs, while focal clonic seizures involve sudden limb movements, beginning on one side of the body and filtering throughout the rest of the body. The inheritance of this disorder is characterized as being autosomal dominant, meaning that while the individual inherited one normal copy of the gene from one parent, they received an abnormal copy from the other parent, effectively producing the presence of the disorder; only one mutated gene is necessary to produce a disorder or disease. Also identified as an autosomal dominant inheritance, the KCNQ3-SLFIE disorder appears during the first year of an infant’s life, and its symptoms typically disappear after 1-2 years (Miceli et al., 2023). Seizure types include focal and generalized seizures, usually lasting 2 minutes; focal seizures are characterized by ‘jerky’ muscle movements, primarily affecting one side of the body, and confusion, while generalized seizures involve sudden movement and stiffness of the limbs, limpness, and unconsciousness. The KCNQ3-NDD is also autosomal dominant in its manifestation, yet it’s described as autosomal dominant de novo, meaning the mutation in the gene is occurring for the first time within the family (Miceli et al., 2023). The parents did not contain mutations in the KCNQ3 gene, and therefore did not pass down the disorder to their child; rather, the mutated gene appeared during the development of the reproductive cells: the egg and the sperm. This disorder is distinguished by seizures, developmental and epileptic encephalopathy (DEE), intellectual disability, and visual impairment, but there is still limited data (Miceli et al., 2023). The presence of DEE results in seizures, which are usually resistant to drug treatments, and encephalopathy, which is associated with the loss of skilled and developmental delays.
Research and Treatment
The rarity of KCNQ3-related disorders and epilepsy results in ongoing research to better understand the disorder. However, there are some methods for providing a diagnosis, such as single gene testing, which involves analyzing the gene sequence to identify splice, missense, or nonsense sites (Miceli et al., 2023). Splice sites refer to the procedure where mRNA, an important factor in producing proper gene expression, is created, resulting in the synthesis of efficient proteins. If a problem is found within this splice site, it could result in faulty expressions of genes and proteins, which, in the case of the KCNQ3 gene, can hinder the productivity of the M-current. Missense sites refer to the sequence of proteins, wherein certain areas, important for the functioning of the protein, are altered, resulting in a disrupted protein and, oftentimes, a disorder. Nonsense sites allude to changes in DNA, which prompt the cessation of protein sequencing and, therefore, non-functional proteins that cause diseases or disorders. Whole exome sequencing (WES) can also be utilized to analyze within the exome, a portion of a genome, which contains exons, or protein-coding areas, that can contain variants or mutations (“Unlocking the Secrets of KCNQ3,” n.d.). Chromosomal microarray analyses may also be conducted to identify developmental delays or intellectual disabilities by discovering deletions or duplications of chromosomes. An electroencephalogram (EEG) is also recommended to identify abnormal brain waves within a patient, which may be able to explain and diagnose seizures in those with epilepsy.
With regards to treatment, seizures resulting from KCNQ3-SLFNE are generally managed with anti-seizure medications (ASMs); common medications include Phenobarbital, Phenytoin, or Carbamazepine (Miceli et al., 2023). For KCNQ3-SLFIE, medications often prescribed are Carbamazepine, Phenobarbital, or Valproate (Miceli et al., 2023). After about 1-3 years, the medications are withdrawn, or stopped from being prescribed, as seizures may cease after 1 year. For KCNQ3-NDD, traditional therapies are recommended, such as speech and physical therapy, to help prevent progressive deterioration of one’s developed skills. Special educational support is also necessary to help the patient reach developmental milestones and other important skills, including motor, verbal, and cognitive abilities, as well as to manage behaviors.
It is important that individuals with KCNQ3-related epilepsies or disorders receive treatment to maintain an improved lifestyle. It may be beneficial to help manage seizures and support one’s developmental skills in order to slow the progression or worsening of the disease’s symptoms.
References
Unlocking the Secrets of KCNQ3-related Developmental Disability (n.d.). Sequencing. https://sequencing.com/education-center/medical/kcnq3-related-developmental-disability
National Library of Medicine. (2011, May 1). KCNQ3 gene. MedlinePlus. https://medlineplus.gov/genetics/gene/kcnq3/#conditions
Families. (2023, March 14). Human Disease Genes. https://humandiseasegenes.nl/kcnq3/families
Miceli, F., et al. (2023, September 28). KCNQ3-Related Disorders. In GeneReviews [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK201978/
