INTRODUCTION
During the past decade, there has been great progress in identifying the genetic basis for human seizure disorders, based largely on the application of research strategies for identifying genes responsible for monogenic disorders1. Positional cloning has been used when large pedigrees with clearcut dominant or recessive inheritance patterns are available. This involves linkage analysis with molecular markers throughout the genome to define a target chromosome region, followed by sequencing genes within the region to detect the causal mutation. The second approach has been to select a ‘candidate gene’ based on its biological function or its known role in related disorders or animal models, and then to test for mutations by sequencing the gene in a group of unrelated individuals with epilepsy.
In spite of substantial progress, the genetic factors involved in most cases of human epilepsy are not known. One likely explanation is that mutations or variants in two or more genes, with interacting effects, are involved in many types of epilepsy. Identification of multiple interacting genes is more difficult than identification of single genes, and this field is in an early stage of development. While indirect evidence suggests that multigenic causality may be very common in human epilepsy, few specific examples have been well documented. In this chapter we describe recent evidence for gene interaction in human epilepsy, and approaches to identifying genetic modifiers that influence disease, in the light of the recently discovered and unanticipated level of rare variation in protein coding sequences. Understanding the interaction between variants in an individual genome is likely to be a major focus of research in the coming years.
Many of the examples discussed here involve genes encoding voltage-gated sodium channels. The structure of this nine-member gene family and its role in epilepsy has recently been reviewed.2 The most common known genetic cause of epilepsy is mutation of the neuronal sodium channel SCN1A. The role of this gene was first identified by positional cloning based on linkage analysis that mapped the epilepsy gene to chromosome 2q24 in two large pedigrees with Generalized Epilepsy with Febrile Seizures Plus (GEFS+).3, 4 Based on our work with sodium channels and epilepsy in the mouse5, we sequenced SCN1A as a positional candidate gene in these two families and identified two causal missense mutations.6 Subsequent functional analysis demonstrated biophysical defects associated with both mutated alleleles.7 After the positional cloning of SCN1A in the GEFS+ families, it was sequenced as a candidate gene for Dravet Syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), a severe, progressive seizure syndrome that occurs as a sporadic trait in patients without a family history. Remarkably, sporadic mutations of SCN1A were identified in a majority of the Dravet Syndrome patients tested.8 GEFS+ and Dravet represent the extremes of a spectrum of SCN1A-associated disorders. Approximately 10% of GEFS+ is accounted for by heterozygous missense mutations of SCN1A, and > 80% of patients with Dravet Syndrome carry heterozygous mutations in SCN1A that include truncation mutations, deletions, and missense mutations.19 More than half of the mutations in Dravet’s syndrome cause loss of channel function 9, 10, demonstrating haploinsufficiency of SCN1A. Spontaneous seizures are also seen in heterozygous mouse models with inactivating mutations of Scn1a.11, 12 More than 700 different mutations of SCN1A have been identified in patients with Dravet Syndrome; their molecular and clinical features are compiled in two recently developed databases.13, 14
Analysis of mouse models provides an experimental system for identification of epilepsy modifier genes. When the same epilepsy mutation is bred onto multiple strains of inbred mice, the severity of the disorder often varies dramatically, due to genetic differences between inbred strains. If the effect of any one modifier gene is sufficiently large, it may be identified by positional cloning in crosses between the inbred strains.15 We have included examples of the use of mouse genetics to detect and analyze gene interaction in seizure disorders.
WITHIN-FAMILY HETEROGENEITY MAY REFLECT THE SEGREGATION OF GENETIC MODIFIERS
It is well known to clinicians that family members with identical genotypes at a disease locus may nonetheless exhibit very different clinical course. One source of phenotypic heterogeneity may be the independent segregation of genetic variants at other loci, so-called “modifier genes”, that exacerbate or ameliorate the effect of the primary mutation.
Variability in Families with Generalized Epilepsy with Febrile Seizures Plus (GEFS+)
An example of intra-familial variation is provided by the GEFS+ pedigree in . Two categories of clinical phenotype are found in this pedigree. Seven affected individuals exhibit mild childhood febrile seizures with no progression, while five affected individuals had febrile seizures that progressed to adult epilepsy.3 The sodium channel mutation SCN1A-Thr875Met was identified in all 12 affected individuals.6 This type of intra-family variation is suggestive of the segregation of a second variant at a modifier locus. If the pedigree is sufficiently large, both primary and modifier genes can be mapped.16
Two distinct phenotypes in affected heterozygous individuals from a GEFS+ family. The SCN1A mutation Thr875Met co-segregates with GEFS+; affected individuals exhibit febrile seizures only (half-filled symbols) or febrile seizures progressing to epilepsy (more...)
Mildly Affected Carriers In a Family with Dravet Syndrome
Deletion or inactivation of sodium channel SCN1A usually results in Dravet’s Syndrome, a haploinsufficiency syndrome that includes severe progressive seizures and impaired cognition.10, 17 Most affected individuals are sporadic cases without affected family members, and are unable to live independently or transmit the defect. However, in 2010 Suls et al described a 4 generation Bulgarian family in which a complete deletion of the SCN1A gene was transmitted through 3 generations.18 Two family members with the deletion exhibit typical, progressive Dravet Syndrome, while two others who transmitted the deletion have moderate epilepsy and are literate and living independently. The authors suggest that the differences in severity between family members may reflect the segregation of one or more genetic modifiers.
Parental Mosaicism in One-Generation Families with Multiplex Dravet Syndrome
The transmission of Dravet Syndrome from an unaffected parent to affected offspring has been observed in approximately 10% of cases. The parent in these families must carry the SCN1A mutation but does not exhibit disease. The possibilty that these individuals carry a protective variant in a modifier gene has been considered. However, a different explanation emerged in a recent study describing genetic mosaicism in the transmitting parent.19 To test for genetic mosaicism, a quantitative, allele-specific PCR assay for the SCN1A mutation was carried out on DNA isolated from the parent’s blood. The proportion of mutant SCN1A allele in different parents was found to vary from 0.04% to 85% of the dose expected in a normal heterozygote, which would be 50%. In one case, reduced dosage was also observed in sperm. The most likely explanation is that the mutations arose de novo during the embryonic development of the parent, resulting in mosaicism of somatic and germ line tissues. If expression of the mutant allele is also reduced in the brain of mosaic individuals, that could account for their mild clinical condition compared to their offspring. Mosaicism was demonstrated for 12 of the 19 cases of transmission of Dravet syndrome examined in this study.
LINKAGE EVIDENCE FOR DIGENIC INTERACTION IN HUMAN EPILEPSY
In rare families, linkage mapping for positional cloning identifies more than one chromosome region related to the epilepsy phenotype. These large families offer the potential for identification of specific pairs of interacting loci. Although the genes have not yet been identified, the linkage data strongly support a 2-gene-interaction mechanism of epilepsy in families such as those described below.
Digenic inheritance of febrile seizures with temporal lobe epilepsy
Linkage analysis was carried out on a 4-generation French family segregating febrile convulsions accompanied by temporal lobe epilepsy.20 Family members included 8 affected individuals with febrile seizures that progressed to afebrile epilepsy, one obligate unaffected carrier, and 9 unaffected family regions, 1q25-31 and 18qter, with significant LOD scores of 2.3 and 3.0, respectively. All of the affected individuals carried the disease-related haplotype at both of these chromosome regions, and none inherited the disease-related haplotype at one region only, strongly indicating digenic inheritance with a requirement for the mutant genes at both loci.
The same investigators studied another 4-generation pedigree segregating febrile seizures in combination with temporal lobe epilepsy or childhood absence epilepsy.21 In this family, the genome-wide linkage scan detected linkage signals on chromosomes 3p and 18p. As above, all patients with febrile seizures and epilepsy shared a common haplotype in both chromosome regions. (The lack of common linked regions in these two families with temporal lobe epilepsy is an indication of the degree of genetic heterogeneity underlying inherited epilepsy.)
Digenic inheritance of epilepsy in families with light sensitivity and myoclonic epilepsy
Pinto and colleagues focused a genome-wide linkage study on 19 families with photo-sensitive epilepsy. Photoparoxysmal response (PPR) is defined by an abnormal EEG response to intermittant photic stimulation. Pinto et al studied sixteen unrelated families with multiple affected members who demonstrated both PPR and epilepsy.22 Two linkage signals of comparable strength were detected on chromosome 7q32 and chromosome 16p13. A subsequent two-locus linkage analysis supported a multiplicative epistasis model in which each locus is necessary but not sufficient to generate the observed phenotypes.23
INTERACTING ION CHANNEL MUTATIONS IN MOUSE MODELS
Since the firing patterns of neurons directly reflect the overall identities and levels of ion channel expression, it is intuitively obvious that the presence of multiple ion channel variants in the same neuron could have a combinatorial effect on firing properties. Genetic interaction between ion channel mutations would be among the most straightforward to interpret. Large scale sequencing of 250 ion channel genes in epilepsy patients and controls identified patients with multiple, potentially-interacting ion channel variants.23a Studies in the mouse provide a system for testing the effects of combining two or more ion channel mutations, with the possibility of examining effects on neuronal activity as well as seizure phenotypes. The examples described below provide proof-of-principle for the types of ion channel interactions that may also contribute to human epilepsy.
Mouse Scn2a and Kcnq2
Mutations in human sodium channel SCN2A and potassium channel KCNQ2 can each cause inherited human epilepsy, but families with variants in both genes have not been described. To test their possible interaction, Kearney et al24 generated mice that were double heterozygotes for a mild mutation of Scn2a and a subclinical mutation of Kcnq2. The combination resulted in mice with severe seizures that died in status epilepticus within 3 weeks after birth. This dramatic example of gene interaction may be understood in terms of the functions of the two channels. The Kcn2q channel is part of a complex that produces a slowly inactivating potassium current that limits neuronal firing rates. Impaired Kcn2q activity would be expected to increase neuronal firing. The Scn2a mutation produced increased persistent current that also predisposes to a reduced threshold for neuronal firing. The presence of both mutant channels in the same cells would act in the same direction towards increased neuronal excitability. Subclinical variants of ion channels in the human population may similarly interact in cases of apparently sporadic epilepsy.
Interaction Between Mouse Scn1a and Scn8a
Mice heterozgyous for null mutations in Scn1a exhibit a spontaneous seizure syndrome that is a model of human Dravet Syndrome.11, 12 The mechanism is thought to involve preferential reduction in firing of inhibitory interneurons in the hippocampus. Martin et al25 generated mice carrying a null allele of Scn1a in combination with a missense mutation of Scn8a that reduces channel activity by shifting the voltage-dependence of activation towards more positive voltages.26 Interestingly, the double heterozygotes carrying both the Scn1a and Scn8a mutations were completely protected from seizures. The reduced activity of excitatory neurons due to the Scn8a mutation may compensate for the reduced activity of inhibitory interneurons due to the Scn1a mutation. This work predicts that mutations of human SCN8A could act as protective modifier variants in individuals inheriting a pathogenic allele of SCN1A. This prediction could be tested in families such as the one in , where the less severely affected individuals might carry a second mutation in SCN8A.
Mouse Calcium Channel Cacna1a and Potassium Channel Kcna1
The calcium channel CACNA1A and the potassium channel KCNA1 (Kv1.1) are both localized in presynaptic terminals of neurons in the thalamus, neocortex and hippocampus. The mouse mutant tottering carries a partial loss-of-function allele of Cacna1a that results in spike wave absence seizures. The null mutation of Kcna1 in the mouse results in juvenile lethality that appears to result from seizures. When these two mutations were combined in double homozygotes, survival was enhanced and seizures were suppressed.27 The authors suggest that the increased excitability of nerve terminals lacking the potassium channel would be countered by the reduction in calcium signaling at the same terminals in the double mutant.
These 3 examples demonstrate that the predicted gene interactions between ion channels can be detected in vivo and can have striking effects on the clinical outcome, as summarized in . The combined effect may be either beneficial or deterimental, depending on the effects of each mutation at the cellular level. These experiments support the possibility that similar interactions will be discovered in human patients, and suggest the value of screening for additional ion channel mutations in families with known channel mutations exhibiting clinical heterogeneity.
Digenic interactions between ion channel mutations in mouse models of epilepsy. a, interaction between mutations in a sodium channel and a potassium channel; b, interaction between mutations in two sodium channels; c, interaction between mutations in (more...)
Human SCN9A as a potential modifier of Dravet Syndrome
SCN1A and SCN9A are adjacent sodium channel genes located on chromosome 2q24.2 A mutation in SCN9A was recently identified in a large Utah pedigree with febrile seizures and no mutation of SCN1A, suggesting that SCN9A can also be responsibile for seizures.28 A followup study of 102 patients with Dravet Syndrome identified seven patients with mutations in both SCN1A and SCN9A28. The SCN1A mutations in the patients included one truncation mutation and three mutations that changed invariant splice site nucleotides, which should be sufficient to cause Dravet Syndrome. The SCN9A mutations were missense mutations that changed amino acid residues that are evolutionarily conserved from chicken to human. The authors suggest that the SCN9A variants may modify the severity of Dravet Syndrome in these patients with primary mutations in SCN1A.
INBRED STRAINS OF MICE PROVIDE ACCESS TO ADDITIONAL MODIFIERS OF EPILEPSY GENES
The inbred strains of mice were generated from wild populations during the past 100 years. Their genomes contain chromosome segments derived from two subspecies of mouse, M. m. domesticus and M. m. musculus. New mutations have accumulated in each strain during decades of laboratory breeding. The differences between any two inbred strains are roughly comparable to the differences between two (outbred) human individuals. Inbred mouse strains provide an experimental opportunity to compare the effects of the same mutation in the context of different genome backgrounds, and thereby to recognize and identify modifier genes responsible for differences between strains. Interstrain variation can also be exploited to isolate genes that influence susceptibility to environmental factors and drugs, as indicated in .
Genetics of complex epilepsy.
Mouse Modifier Genes and Human Epilepsy
The conservation of basic mammalian neurobiology suggests that similar mutations would have similar effects on seizures in human and mouse. However, it is not known a priori whether an identified mouse modifier gene is represented by genetic variation in the human population. The practical impact of modifiers discovered in the mouse will depend on whether corresponding mutations have arisen during human history and are represented in modern human genomes.
This chapter has focused on the detection of modifier mutations influencing seizure disorders whose primary cause is a single gene mutation with a large functional effect. In polygenic or ‘complex’ epilepsy, multiple susceptibility mutations with individually small effects combine to produce an epileptic phenotype. Polygenic inheritance is thought to be a major cause of common human epilepsies. Recent reviews address polygenic inheritance of epilepsy in human and mouse.35
36
FUTURE PROSPECTS FOR UNDERSTANDING GENE INTERACTION IN HUMAN EPILEPSY
The genetic basis for most cases of human epilepsy remains unknown, in spite of recent successes in identifying the roles of SCN1A and related ion channels. This situation is likely to change dramatically in the near future with the introduction of individual genome sequencing. Using inexpensive, high-throughput “NextGen” sequencing technology, > 90% of the 180,000 exons in the human genome can be sequenced from individual samples. The first few exomes published in 2009 and 2010 revealed that each of us carry approximately 250 rare amino acid sequence variants not previously described.
These include benign variants without functional consequences as well as mutations causing significant loss of function. By revealing all of their genetic variants, genome sequencing of epilepsy patients will accelerate the discovery of primary disease genes as well as genetic modifiers. The urgent challenge will then be to recognize the subset of amino acid substitutions that change the function of the encoded protein. In a recent example using whole genome sequencing, a patient was identified with infantile epileptic encephalopathy caused by a de novo mutation of the sodium channel SCN8A.37 The same patient carried compound heterozygous mutations in two genes active in the nervous system, NRP2 and UNC13C, that may have contributed to the clinical course of the disease. Functional assays to distinguish between benign and pathogenic variants will be an increasingly important component of epilepsy research, in order to interpret the abundance of genetic information. Identification of additional epilepsy genes and their genetic modifiers will provide new targets for intervention and should lead to more effective treatments for seizure disorders.
ACKNOWLEDGEMENTS
Support was provided by NIH grants R01 NS34509 (MHM) and T32 GM007544 (JEO).
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