Alternative titles; symbols
HGNC Approved Gene Symbol: KCNQ2
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): 20:63,400,208-63,472,655 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Developmental and epileptic encephalopathy 7 | 613720 | Autosomal dominant | 3 |
| Myokymia | 121200 | Autosomal dominant | 3 | |
| Seizures, benign neonatal, 1 | 121200 | Autosomal dominant | 3 |
The KCNQ2 gene encodes a voltage-gated potassium channel that is expressed in the brain (Biervert et al., 1998).
In the course of a search for the mutational basis of benign familial neonatal seizures (BFNS1; 121200) mapping to chromosome 20, Singh et al. (1998) identified a novel voltage-gated potassium channel gene that showed significant homology to KVLQT1 (also known as KCNQ1 and KCNA9), the chromosome 11 potassium channel gene responsible for long QT syndrome-1 (192500) and a form of Jervell and Lange-Nielsen cardioauditory syndrome (220400). A single cDNA isolated with the D20S24 probe in this region showed significant homology with KVLQT1. Singh et al. (1998) found that the KCNQ2 cDNA hybridized to transcripts of approximately 1.5, 3.8, and 9.5 kb on Northern blots made from brain.
By positional cloning from the 20q13.3 region where 1 form of benign familial neonatal seizures is known to map, Biervert et al. (1998) independently isolated the KCNQ2 gene and found that it was expressed in brain.
Yang et al. (1998) described the cloning, tissue distribution, and functional expression of KCNQ2 and KCNQ3 (602232), both of which are associated with benign neonatal epilepsy. The deduced 871-amino acid KCNQ2 protein has features of a voltage-gated potassium channel. Northern blot analysis of 8 human tissues detected an 8.5-kb KCNQ2 transcript in brain only. Within brain, highest expression of KCNQ2 was detected in cerebellar cortex, amygdala, caudate nucleus, and hippocampus.
Biervert and Steinlein (1999) determined that the KCNQ2 gene has at least 18 exons, occupying more than 50 kb of genomic DNA. Splice variants were identified. For example, in fetal brain, exon 8 was absent in all transcripts, while this exon was present in clones derived from adult brain RNA.
Biervert et al. (1998) found that expression of human KCNQ2 in Xenopus laevis oocytes led to potassium-selective currents that activated slowly with depolarization.
The M channel is a slowly activating and deactivating potassium conductance that plays a critical role in determining the subthreshold electroexcitability of neurons as well as the responsiveness to synaptic inputs. The M current was first described in peripheral sympathetic neurons, and differential expression of this conductance produces subtypes of sympathetic neurons with distinct firing patterns. The M channel is also expressed in many neurons in the central nervous system. Wang et al. (1998) showed that the KCNQ2 and KCNQ3 channel subunits can coassemble to form a channel with essentially identical biophysical properties and pharmacologic sensitivities to the native M channel and that the pattern of KCNQ2 and KCNQ3 gene expression is consistent with these genes encoding the native M channel.
Yang et al. (1998) demonstrated that KCNQ2 and KCNQ3, both of which are associated with benign neonatal epilepsy, interact functionally with each other and with KCNE1 (176261), which is mutant in a form of Jervell and Lange-Nielsen syndrome and in 1 form of long QT syndrome.
Cooper et al. (2000) provided information regarding the in vivo distribution and biochemical characteristics of human brain KCNQ2 and KCNQ3, the 2 channel subunits that form M channels when expressed in vitro, and, when mutated, cause the dominantly inherited epileptic syndrome, benign familial neonatal seizures. They found that the KCNQ2 and KCNQ3 proteins are colocalized in a somatodendritic pattern on pyramidal and polymorphic neurons in the human cortex and hippocampus. Immunoreactivity for KCNQ2, but not KCNQ3, is also prominent in some terminal fields, suggesting a presynaptic role for a distinct subgroup of M channels in the regulation of action potential propagation and neurotransmitter release. KCNQ2 and KCNQ3 could be coimmunoprecipitated from brain lysates. Further, both proteins were coassociated with tubulin (see 602529) and protein kinase A (see 176911) within a triton X-100-insoluble protein complex. Cooper et al. (2000) suggested that these studies provided a view of a signaling complex that may be important for cognitive function as well as epilepsy, and that analysis of this complex may shed light on the transduction pathway linking muscarinic acetylcholine receptor (see 118510) activation to M-channel inhibition.
By recording channel currents produced in cRNA-injected Xenopus oocytes, Zhang et al. (2003) found that phosphatidylinositol (4,5)-bisphosphate (PIP2) activated all members of the KCNQ channel family analyzed, including human KCNQ2 and heterodimers of human KCNQ2 and rat Kcnq3. Similar results were obtained with mammalian cells expressing KCNQ2 and Kcnq3. Mutation of his328-to-cys in KCNQ2 and his330-to-cys in Kcnq3 reduced or eliminated PIP2-mediated channel activation. Wortmannin, a pharmacologic inhibitor of PIP2 regeneration, slowed the recovery from PIP2 hydrolysis and decreased the sensitivity of the KCNQ2/Kcnq3 channel to PIP2. Zhang et al. (2003) concluded that PIP2 acts as a membrane-diffusible second messenger to regulate the activity of KCNQ currents.
Benign Familial Neonatal Seizures 1
In affected members of a family with benign familial neonatal seizures-1 (BFNS1; 121200), Singh et al. (1998) identified a small deletion on chromosome 20q encompassing the KCNQ2 gene. The finding was confirmed by fluorescence in situ hybridization in an affected individual who presented with seizures beginning at 3 days and had 118 generalized seizures until the age of 23 days. A single seizure was observed at 3.5 months in conjunction with an acute infection of the middle ear with fever, but no seizures were observed thereafter. Singh et al. (1998) also identified different heterozygous mutations in the KCNQ2 gene (see, e.g., 602235.0001 and 602235.0002) in additional families with BFNS1.
In a large pedigree with BFNS1, Biervert et al. (1998) found a 5-bp insertion (602235.0003) that was predicted to delete more than 300 amino acids from the C terminus of KCNQ2. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization was indicated as the cause of this age-specific epileptic syndrome.
Dedek et al. (2001) reported a Caucasian family in which BFNS was followed later in life by myokymia, involuntary contractions of skeletal muscles (see 121200). All affected members of the family carried an arg207-to-trp mutation (R207W; 602235.0006) that neutralized a charged amino acid in the S4 voltage-sensor segment of KCNQ2. This substitution led to a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. Myokymia was thought to result from hyperexcitability of the lower motoneuron; indeed both KCNQ2 and KCNQ3 mRNAs were detected in the anterior horn of the spinal cord where the cells of the lower motoneurons arise. Dedek et al. (2001) proposed that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explained by this particular KCNQ2 mutant caused myokymia in addition to BFNC. Wuttke et al. (2007) identified a mutation in the KCNQ2 gene (R207Q; 602235.0011) in a patient with isolated myokymia.
Heron et al. (2007) identified 3 deletions and 1 duplication of more than 1 exon of the KCNQ2 gene in 4 (44%) of 9 unrelated families with benign familial neonatal seizures who had previously tested negative for coding or splice site mutations. The changes were predicted to result in haploinsufficiency. The authors suggested that multiplex ligation-dependent probe amplification (MLPA) should be a second-tier testing strategy in candidate cases.
Developmental and Epileptic Encephalopathy 7
In a boy with developmental and epileptic encephalopathy-7 (DEE7; 613720), Dedek et al. (2003) identified a heterozygous missense mutation in the KCNQ2 gene (S247W; 602235.0008). Functional expression studies showed that the S247W mutation reduced channel currents by more than 50% in homomeric KCNQ2 channels. The mutation was inherited from his mother, who had a milder phenotype with resolution of seizures in infancy and subsequent normal development. The son had onset of seizures at day 3 of life and the mother at age 1 month. Dedek et al. (2003) emphasized that some KCNQ2 mutations may be associated with a more severe phenotype than is typical for BFNS.
Weckhuysen et al. (2012) identified 7 different heterozygous mutations in the KCNQ2 gene (see, e.g., 602235.0012-602235.0014) in 8 (10%) of 80 patients with neonatal or early infantile seizures and associated psychomotor retardation. The mutations arose de novo in 7 cases; in 1 case, a severely affected patient inherited the mutation from her father, who had a milder phenotype and was mosaic for the mutation.
Saitsu et al. (2012) identified 3 different de novo missense mutations in the KCNQ2 gene (see, e.g., A265V, 602235.0015) in 3 of 12 Japanese patients with DEE and onset of seizures in the first week of life. The mutations were found by whole-exome sequencing. The findings suggested that KCNQ2 mutations may be a common cause of this disorder. Functional studies of the variants were not performed.
By high-resolution melting analysis or whole-exome sequencing of 239 patients with DEE, Kato et al. (2013) found that 12 patients carried a total of 10 heterozygous missense mutations in the KCNQ2 gene. The mutations occurred de novo in all patients except 1, who inherited the mutation from her mildly affected mother who was somatic mosaic for the mutation. Several of the mutations had previously been reported (see, e.g., A265V, 602235.0015), but functional studies were not performed.
The electroconvulsive threshold (ECT) test has been used extensively to determine the protection conferred by antiepileptic drug candidates against induced seizures in rodents. Yang et al. (2003) adopted the ECT test to screen the progeny of ethylnitrosourea-treated male C57BL/6J mice. In a small-scale screen, several mutant lines conferring a low threshold to ECT minimal clonic seizures were mapped to the telomeric region of mouse chromosome 2 in independent founder families. Genetic and physical mapping data indicated that several lines shared a single mutation, Szt1 (seizure threshold-1), consisting of a 300-kb deletion of genomic DNA involving 3 known genes. Two of these genes, Kcnq2 and Chrna4 (118504), are known to be mutated in human epilepsy families. Szt1 homozygotes and heterozygotes displayed similar phenotypes to those found in the respective Kcnq2 knockout mutant mice, suggesting that Kcnq2 haploinsufficiency may lie at the root of the Szt1 seizure sensitivity.
In affected members of a family with benign familial neonatal seizures (BFNS1; 121200), Singh et al. (1998) demonstrated a TAC-to-TGC transition converting codon 284 from tyrosine to cysteine. The family was too small to permit demonstration of linkage to chromosome 20. The mutation occurred in the pore region of the channel.
In kindred 1705, Singh et al. (1998) demonstrated that individuals affected with benign familial neonatal seizures (BFNS1; 121200) had an ala306-to-thr (A306T) amino acid substitution in the S6 transmembrane segment. This alanine residue was conserved in all members of the Shaker, Shab, Shaw, and Shal subfamilies of potassium channels.
Biervert et al. (1998) identified an insertional mutation in the KCNQ2 gene in a large Australian Caucasian pedigree with benign familial neonatal seizures (BFNS1; 121200) previously reported by Berkovic et al. (1994). Biervert et al. (1998) found a heterozygous 5-bp insertion at the triplet encoding amino acid 534 in a segment highly conserved between KCNQ2 and KCNQ1 (607542), which is mutated in type 1 long QT syndrome (192500). The resulting frameshift was predicted to cause a premature stop, which would truncate more than 300 amino acids. Of 13 affected family members, 10 had known neonatal seizures. Two patients had afebrile seizures later, 1 of whom did not have neonatal seizures. One mutation carrier was unaffected, indicating reduced penetrance. Berkovic et al. (1994) noted the phenotypic heterogeneity in this family.
In a patient with benign familial neonatal seizures (BFNS1; 121200), Biervert and Steinlein (1999) identified a 1-bp deletion, 1846delT, in the KCNQ2 gene that caused a frameshift in exon 16, removing 228 amino acids from the predicted wildtype sequence and replacing them with a stretch of 283 amino acids showing a completely different sequence. The mutation was also present in the DNA sample obtained from the father but not in that from the mother. The paternal grandmother reportedly had also suffered from neonatal seizures but was not available for study.
In a 4-generation Italian family segregating benign familial neonatal seizures (BFNS1; 121200), Miraglia Del Giudice et al. (2000) identified a 686C-T mutation in exon 3 of the KCNQ2 gene, resulting in an arg214-to-trp substitution. The mutation was found in the 8 affected members of the pedigree and in 1 unaffected subject who was an obligate carrier. The mutation occurred in the transmembrane domain S4, neutralizing one of the conserved, positively charged residues of that segment. The substitution abolished an AgeI restriction site and was not detected in 150 Italian controls.
In 5 affected members of a Caucasian family with benign familial neonatal seizures and/or myokymia (see 121200), Dedek et al. (2001) identified a heterozygous C-to-T transition in exon 3 of the KCNQ2 gene, resulting in an arg207-to-trp (R207W) substitution in the fourth transmembrane domain. Three mutation carriers had BFNS with myokymia, 1 had isolated myokymia without seizures, and 1 had neonatal seizures with no clinical signs of myokymia, although electromyography demonstrated spontaneous discharges of grouped motor unit potentials. In vitro functional expression studies showed that the mutation resulted in a shift of voltage-dependent activation of KCNQ2 and a dramatic slowing of activation upon depolarization. The loss of potassium current was more severe compared to other KCNQ2 mutations and showed a dominant-negative effect.
In a patient with isolated myokymia and no history of neonatal seizures, Wuttke et al. (2007) identified an R207Q mutation (602235.0011) in the same codon as the R207W mutation. In vitro functional expression studies showed that mutant R207W and R207Q channels had large depolarizing shifts and marked slowing of activation time compared to wildtype channels. Coexpression with wildtype channels showed a dominant-negative effect reducing the current amplitude by 70% after short depolarization.
In 4 affected members of a family with benign familial neonatal seizures (BFNS1; 121200), Borgatti et al. (2004) identified a heterozygous 1620G-A transition in the KCNQ2 gene, resulting in a lys526-to-asn (K526N) substitution in the C-terminal region of the protein. The mutation is located in a highly conserved region within alpha-helix B that is necessary for calmodulin binding. Functional expression studies showed that the K526N mutation decreased the voltage-dependence of the channel. Although 2 patients had a phenotype consistent with typical BFNS, the other 2 patients had a complex phenotype that was atypical and severe, consistent with developmental and epileptic encephalopathy (DEE7; 613720). One developed an extremely unfavorable outcome, profound mental retardation, and spastic quadriparesis. The other continued to have focal seizures until late infancy with a moderate degree of mental retardation and a mild cerebellar syndrome. Borgatti et al. (2004) noted that some patients with BFNS may experience seizures later in life or a different set of epileptic subtypes sometimes associated with severe neurologic and intellectual impairment. Overall, the clinical, genetic, and functional data did not provide a definitive explanation for the wide range of phenotypic variability observed in the described family, therefore preventing genotype-phenotype correlations. The authors postulated that the phenotypic variability could be due to the interplay of pathogenic mutations, modifier genes, and more subtle environmental factors.
In a boy with developmental and epileptic encephalopathy-7 (DEE7; 613720), Dedek et al. (2003) identified a heterozygous C-to-G transversion in exon 5 of the KCNQ2 gene, resulting in a ser247-to-trp (S247W) substitution in the fifth transmembrane residue of the protein. The mutation was not identified in 202 control chromosomes. Functional expression studies showed that the S247W mutation reduced channel currents by more than 50% in homomeric KCNQ2 channels. The mutation was inherited from his mother, who had a milder phenotype with resolution of seizures in infancy and subsequent normal development. The son had onset of seizures at day 3 of life and the mother at age 1 month. Dedek et al. (2003) emphasized that some KCNQ2 mutations may be associated with a more severe phenotype than is typical for BFNS.
In 9 affected members of a large Italian family with benign familial neonatal seizures (BFNS1; 121200), Bassi et al. (2005) identified a heterozygous 10-bp deletion and 1-bp insertion (761del10insA) in cis in the KCNQ2 gene, resulting in a truncated N-terminal peptide of 194 residues. The resultant mutant protein lacks the S4 domain, which is critical for voltage sensing. In vitro functional expression studies showed that the mutant KCNQ2 subunit was unable to form functional homomeric potassium channels, suggesting haploinsufficiency rather than a dominant-negative effect. One affected family member developed severe epilepsy associated with mild mental retardation and persistent neurologic problems in adult life; this phenotypic variability was considered by the authors to be consistent with the fact that 10 to 15% of BFNS individuals experience seizure manifestations later in life.
In affected members of a family with benign familial neonatal seizures (BFNS1; 121200), originally reported by Rett and Teubel (1964), Zimprich et al. (2006) identified a heterozygous 1-bp deletion (2127delT) in the last exon of the KCNQ2 gene, resulting in a replacement of the C terminus with 219 new amino acids and a protein that is 56 residues longer than the wildtype protein. Three of the 9 affected individuals later developed childhood nocturnal generalized tonic-clonic seizures; 2 of the 3 also had simple focal orofacial seizures.
In a 25-year-old Egyptian man with isolated myokymia (see 121200), Wuttke et al. (2007) identified a heterozygous G-to-A transition in the KCNQ2 gene, resulting in an arg207-to-gln (R207Q) substitution in a highly conserved residue in the voltage sensor region of the potassium channel. He had no history of neonatal seizures and no family history of epilepsy or peripheral nerve hyperexcitability. Clinically, he had permanent muscle overactivity in the distal upper extremities and small amplitude movements of the fingers, which were not disabling. However, he also reported exercise-induced cramps of both hands since childhood and 4 episodes of exercise-induced generalized muscle stiffness. EMG showed spontaneous irregular discharges consistent with myokymia. Wuttke et al. (2007) noted that a mutation in the same codon (R207W; 602235.0006) had been associated with neonatal epilepsy and/or myokymia. In vitro functional expression studies showed that mutant R207W and R207Q channels had large depolarizing shifts and marked slowing of activation time compared to wildtype channels. Coexpression with wildtype channels showed a dominant-negative effect reducing the current amplitude by 70% after short depolarization.
In a girl with developmental and epileptic encephalopathy (DEE7; 613720), Weckhuysen et al. (2012) identified a heterozygous 638G-A transition in the KCNQ2 gene, resulting in an arg213-to-gln (R213Q) substitution at a highly conserved residue in the transmembrane domain. The mutation was not found in 276 control individuals. The patient had onset of multiple daily seizures on the second day of life, and the mother had noted jerking movements during pregnancy. The patient had poor response to treatment, but the seizures remitted at age 14 months. However, at age 2 years 10 months, she had severe psychomotor retardation, could not roll over, was nonverbal, had severe spastic quadriplegia, and some dysmorphic features. Her father, who had benign neonatal seizures and myokymia, was mosaic for the mutation, which was found in 30% of his lymphocytes.
In a 9-year-old boy with developmental and epileptic encephalopathy (DEE7; 613720), Weckhuysen et al. (2012) identified a de novo heterozygous 1636A-G transition in the KCNQ2 gene, resulting in a met546-to-val (M546V) substitution at a highly conserved residue in one of the calmodulin binding domains in the C-terminal region. The mutation was not found in 276 control individuals. On the third day of life, the patient had onset of multiple daily tonic seizures resistant to treatment and associated with a burst suppression pattern on EEG that evolved into multifocal epileptic activity. Seizures remitted at age 3 years and the EEG was normal at age 8. However, he had psychomotor retardation, mild spasticity, widely spaced gait, and lack of speech development. Brain imaging showed lesions in the basal ganglia and a thin posterior corpus callosum.
In 2 unrelated patients with developmental and epileptic encephalopathy (DEE7; 613720), Weckhuysen et al. (2012) identified a de novo heterozygous 869G-A transition in the KCNQ2 gene, resulting in a gly290-to-asp (G290D) substitution at a highly conserved residue in the transmembrane domain. The mutation was not found in 276 control individuals. Both patients had onset of multiple daily tonic seizures on the second day of life, but the seizures remitted at around age 3 years. EEG studies were abnormal at first, but normalized over time. Both patients showed psychomotor retardation and were nonverbal. One had axial hypotonia and widely spaced gait, whereas the other had spastic quadriparesis.
In a 3-month-old Japanese boy with developmental and epileptic encephalopathy (DEE7; 613720), Saitsu et al. (2012) identified a de novo heterozygous c.794C-T transition in the KCNQ2 gene, resulting in an ala265-to-val (A265V) substitution. The patient developed tonic spasms on the first day of life and then had intractable seizures associated with a suppression-burst pattern on EEG; he was diagnosed clinically with Ohtahara syndrome. He had delayed development and no eye pursuit. The patient was 1 of 12 probands with a similar disorder who underwent whole-exome sequencing. Functional studies were not performed.
Kato et al. (2013) identified a de novo heterozygous A265V substitution in 2 unrelated Japanese patients with DEE7. The mutations, which were found by whole-exome sequencing, were not present in 212 control exomes. Onset of seizures in both patients occurred in the early neonatal period.
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