Molecular Pathogenesis
The KCNQ potassium channel gene subfamily consists of five members (KCNQ1-5), each encoding a subunit of a voltage-gated potassium channel. Each subunit shows distinct tissue distribution and subcellular localization, as well as biophysical, pharmacologic, and pathophysiologic properties [Soldovieri et al 2011].
KCNQ subunits, similar to other voltage-gated potassium channel subunits, include six transmembrane domains, with cytoplasmic N-terminal (short) and C-terminal (longer) regions. In neurons, KCNQ2, KCNQ3, KCNQ4, and KCNQ5 subunits (either as homomultimers or heteromultimers) represent the molecular basis of the M-current (IKM), a K+-selective, noninactivating, and slowly activating/deactivating current [Brown & Adams 1980, Wang et al 1998], showing a critical role in spike-frequency adaptation and neuronal excitability control.
In addition to KCNQ3, all other KCNQ genes have a role in human genetic disease:
KCNQ5. Widely distributed in brain, skeletal muscle, and smooth muscle. Pathogenic variants have been found in four unrelated individuals with intellectual disability, two of whom also have epilepsy [
Lehman et al 2017].
Gene structure. The human KCNQ3 transcript has 16 exons.
At least four transcript variants are known; their functional roles and differences are unknown.
Transcript variant 1 (
NM_004519.3; 11266 bp) is the predominant isoform, containing 15 exons; it encodes isoform 1 of the KCNQ3 channel, consisting of 872 aa (
NP_004510.1), and is by at least tenfold the most expressed form in all tissues.
Several additional minor
isoforms are generated by combinations of alternative first-
exon use and alternative
splicing of the 3’ exons.
For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. The first pathogenic variant in KCNQ3 was described in 1998 [Charlier et al 1998]. Table 2 lists the variants currently associated with KCNQ3-related seizure disorders. Whenever possible, a short comment on the functional consequences of each variant is given, along with interpretation based on current understanding of the disorder.
Table 2.
Overview of the Available Genetic, Clinical, and Functional Data from Families with KCNQ3 Variants: BFNE, BFIE, and Other Complex Neurologic Phenotypes
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DNA Nucleotide Change | Predicted Protein Change | Localization | BFNE | BFIE | Additional Clinical Data | Functional Effects | References |
---|
c.680G>A | p.Arg227Gln | | | | ID (no details provided) | |
McRae et al [2017]
|
c.688C>T | p.Arg230Cys | S4 | ‒ | ‒ | Variant found in 4 unrelated persons, all de novo, in studies focused on different phenotypes:
Epi4K: epileptic encephalopathy Bosch: ID, cortical visual impairment, & absence seizures DDD consortium: ID
Phenotypic details not yet available | Stabilization of the activated state, producing a gain-of-function effect | Rauch et al [2012], Allen et al [2013], Bosch et al [2016], Miceli et al [2015a], McRae et al [2017] |
c.835G>T | p.Val279Phe | S5 | + | ‒ | | ↓ in current amplitude when expressed w/KCNQ2; no significant difference when expressed w/KCNQ2 & KCNQ3 |
Maljevic et al [2016]
|
c.895G>A | p.Glu299Lys | S5-S6 linker region; pore | + | ‒ | Variant segregates w/BFNE phenotype in 4/5 sibs of a 3-generation family; possibly contributes to the rolandic epilepsy in this family. | Reduction in current amplitude | Neubauer et al [2008]; Hahn & Neubauer [2009] |
c.914A>G | p.Asp305Gly | + | ‒ | | Reduced current amplitude of heteromeric channels |
Singh et al [2003]
|
c.923G>C | p.Trp308Ser | + | ‒ | Mother (not tested) w/neonatal & febrile seizures | |
Sands et al [2016]
|
c.925T>C | p.Trp309Arg | + | ‒ | | Homomeric channels lacked potassium current & heteromeric channels displayed a dramatic reduction of current. | Hirose et al [2000]; Uehara et al [2008]; Sugiura et al [2009] |
c.929G>T | p.Gly310Val | + | ‒ | | |
Charlier et al [1998]
|
c.950T>C | p.Ile317Thr | + | ‒ | Moderate psychomotor delay in some family members | Reduction in current amplitude |
Soldovieri et al [2014]
|
c.988C>T | p.Arg330Cys | + | ‒ | Same variant detected in 2 unrelated families | Homomeric channels lacked potassium current & no significant difference in current amplitude when expressed w/KCNQ2 & KCNQ3. | Li et al [2006]; Li et al [2008]; Fister et al [2013]; Miceli et al [2015b] |
c.989G>T | p.Arg330Leu | + | ‒ | Moderate psychomotor delay in several family members | Homomeric channels lacked potassium current & reduction of current amplitude when expressed w/KCNQ2 & KCNQ3. |
Miceli et al [2015b]
|
c.989G>A | p.Arg330His | + | ‒ | | |
Allen et al [2014]
|
c.1019G>T | p.Gly340Val | S6 region | + | ‒ | | |
Grinton et al [2015]
|
c.1066G>A | p.Ala356Thr | ‒ | ‒ | ID (no details provided) | |
McRae et al [2017]
|
c.1091G>A | p.Arg364His | C-terminus | ‒ | + | Late-infantile staring spells at age 2 yrs, generalized convulsive seizures & CTS on EEG | |
Fusco et al [2015]
|
c.1142C>T | p.Ala381Val | ‒ | ‒ | Variant occurred in 2 sibs w/rolandic epilepsy (no neonatal seizures), but was also present in their unaffected mother; a very rare allele, absent in the gnomad database of 250K alleles. | No functional effect; variant of unknown significance |
Neubauer et al [2008]
|
c.1403A>G | p.Asn468Ser | ‒ | + | All 3 sibs w/the variant were affected. Chinese ethnicity; variant is present in 0.06% of East Asians (gnomAD) | No functional effect; variant of unknown signficance ‒ although low penetrance is established, a partial contribution cannot be excluded. |
Singh et al [2003]
|
c.1657G>A | p.Gly553Arg | | | ID (no details provided) | |
McRae et al [2017]
|
c.1720C>T | p.Pro574Ser | + | ‒ | Allele is present at 0.3% in non-Finnish Europeans & 0.2% in Latinos (gnomAD). Overrepresented (p=0.008) in idiopathic generalized epilepsies (8/455 persons). Detected in other complex phenotypes; in 4 persons w/rolandic epilepsy & in 1 w/rolandic epilepsy & moderate psychomotor delay; in 3 persons w/autism spectrum disorders & no additional neurologic features | No functional effect; reduced current amplitude only when coexpressed w/KCNQ5. Variant of unknown signficance ‒ although low penetrance is established, a partial contribution cannot be excluded. | Neubauer et al [2008]; Hahn & Neubauer, [2009]; Miceli et al [2009]; Lemke et al [2012]; Gilling et al [2013] |
c.2263G>A | p.Asp755Asn | ‒ | ‒ | Variant occurred in 2 sibs: 1 w/rolandic epilepsy (no neonatal seizures), 1 w/EEG features (CTS) but no seizures. Also occurred in the unaffected mother & was absent in a sib w/rolandic epilepsy; is present in 0.07% of Europeans, incl 1 homozygous individual (gnomAD). | Variant of unknown significance |
Neubauer et al [2008]
|
c.2338C>T | p.Arg780Cys | ‒ | + | | |
Zara et al [2013]
|
c.2462A>G | p.Asn821Ser | + | ‒ | Found in a typical family w/BFNE who also had a KCNQ2 deletion/insertion (likely pathogenic); the KCNQ3 variant does not cosegregate w/the disease. | No difference versus wt; likely non-pathogenic variant |
Bassi et al [2005]
|
Deletion of exons 1-15 | | + | ‒ | Neonatal seizures followed by rolandic epilepsy in proband & maternal grandfather | |
Sands et al [2016]
|
BFIE = benign familial infantile epilepsy; BFNE = benign familial neonatal epilepsy; CTS = centrotemporal spikes; FS = febrile seizures; ID = intellectual disability
Reference sequences: NM_004519.3 (KCNQ3), cDNA numbering begins with +1 as the A of ATG initiation codon.
Normal gene product.
KCNQ3 encodes a voltage-gated potassium channel subunit (KCNQ3 or Kv7.3) mainly expressed in neurons. KCNQ3 appears unable to form a ion-conducting channel by itself, but must coassemble with KCNQ2, KCNQ4, or KCNQ5.
KCNQ3/KCNQ2 heteromers are believed to be the main constituents underlying a K+ current, called M-current, which plays important roles in controlling excitability in many central and peripheral neurons [Delmas & Brown 2005]. M-current activation reduces neuronal excitability by stabilizing the membrane potential at values closer to the equilibrium potential for K+ ions, thus limiting repetitive firing and contributing to spike frequency adaptation. M-current, somewhat paradoxically, can also augment excitability under some conditions, by enhancing availability of the sodium channels driving the neuronal action potential [Battefeld et al 2014]. M-currents are present on both excitatory principal cells and inhibitory interneurons [Lawrence et al 2006, Battefeld et al 2014]. The complexity of M-current roles, which may change with human development, are factors contributing to the phenotypic heterogeneity and age dependence associated with KCNQ3.
Abnormal gene product. Except for one small pedigree with an intragenic deletion [Sands et al 2016], all known pedigrees with KCNQ3-related epilepsy have missense variants. Heterozygous KCNQ3 complete loss may usually be tolerated, since there are 11 splice site, frame shift, and stop gain variants in the gnomAD control dataset. This stands in contrast to KCNQ2-related BFNE, where about two thirds of pedigrees have large intragenic deletions, splice site, frame shift, and stop gain variants [Millichap et al 2016], and only one such allele (also found in a large BFNE pedigree) is present in gnomAD. Thus, KCNQ3 pathogenicity appears usually to result from the expression of variant KCNQ3 subunits that alter the activity of heteromeric channels.
A series of missense KCNQ3 variants identified in BFNE pedigrees have been shown to reduce KCNQ2/KCNQ3 current, but the quantitative reduction does not appear to strictly correlate with seizure duration or presence of developmental disability. Most BFNE-causing KCNQ3 variants (e.g., p.Glu299Lys, p.Asp305Gly, p.Gly310Val, and p.Arg330Cys) caused a 20%-40% reduction in current, but expression of KCNQ3 p.Tyr309Arg reduced heteromeric channel function by about 60%, suggesting a dominant-negative effect. No obvious phenotypic differences were seen between those families. In addition, two KCNQ3 variants (p.Arg330Leu and p.Ile317Thr) described in pedigrees including individuals with BFNE symptoms in infancy but subsequent moderate psychomotor delay caused a variable decrease (between 30% and >60%) in aspects of channel function [Soldovieri et al 2014, Miceli et al 2015b].
The KCNQ3 variant p.Arg230Cys, recently identified as occurring de novo in four individuals with phenotypes including epileptic encephalopathy and intellectual disability with or without seizures and cortical visual impairment, is located outside the pore domain, in the voltage-sensor. Functional studies have demonstrated an opposite effect to variants causing BFNE. KCNQ3 variant p.Arg230Cys stabilized the channel open state, thereby producing a gain-of-function effect [Miceli et al 2015a]. Owing to small patient numbers, incomplete clinical information, and complex functional profiles of the known KCNQ3 variants, definitive conclusions about potential genotype-phenotype correlations cannot be drawn at this stage.