Penetrance and Expressivity of Genes Involved in the Development of Epilepsy in the Genetically Epilepsy-Prone Rat (GEPR)

Abstract

In order to understand the level of complexity of the epileptic phenotype in the two strains of Genetically Epilepsy-Prone Rats (GEPRs), we determined two important measures of genetic complexity, penetrance and expressivity. Penetrance is the percentage of animals of a specific genotype who express the phenotype associated with that underlying genotype. Expressivity refers to the degree that a particular genotype is expressed as a phenotype within an individual. Incomplete penetrance and variable expressivity are caused by genetic and environmental variation. In this paper we have studied the epileptic phenotype for 20,373 rats. Animals were tested on three occasions for audiogenic seizure and given an audiogenic response score (on a scale of 0-9, 0 being no seizure and 9 being the most severe). The GEPR-3 and GEPR-9 animals both show incomplete penetrance and variable expressivity of the underlying genetic predisposition. The GEPR-9 strain has more animals that have variable levels of seizure predisposition (as measured by a scoring system that denotes the severity of generalized tonic/clonic seizures) and a greater percentage of animals that exhibit no susceptibility to such seizures induced by sound. Both strains have a number of animals that are not susceptible to sound-induced GTCSs and that exhibit some variability in seizure severity. The GEPR-9 males show greater differences in expressivity and penetrance compared to GEPR-9 females. The GEPR-3 animals also show sex-associated variable penetrance and expressivity of the epileptic phenotype, although the differences are much smaller. These findings are the first step toward the mapping of the underlying quantitative trait loci (QTL) for seizure in these animals.

The Krushinsky-Molodkina rat strain: The study of audiogenic epilepsy for 65 years

“…Blood flow anomalies in the brain, postictal to catalepsy, the changes in AS intensity as the result of antioxidant treatment in KM rat strain -these findings, we believe, are still of interest for those who study AS in rats and mice. At the same time, the "isolated" development of KM rat strain studies and their results proved the generality of the audiogenic epilepsy patterns and their physiological "rules" of development [99][100][101][102][103][104][105][106][107][108][109][110][111]. These facts should encourage investigators for joint efforts for the intensive study of this model of human epilepsy, the cause of misfortune and suffering for so many people.…”

“…It was also stated [12] that AS in GEPRs was inherited as a dominant autosomal trait [102]. The first stages of WAR strain selection were described, which evidenced the significant influence of genetics on this trait determination [11].…”

Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs

“…Such a particular trait appears to mimic a partial seizure secondarily generalized to tonic-clonic seizures and is considered of potential clinical relevance. Both groups of GEPR show a complex interaction among multiple genes [86].…”

“…Males of the GEPR-9 strain have lesser differences in expressivity and penetrance in comparison to females of the GEPR-9 strain. When the epileptic phenotype is evaluated, GEPR-3 shows sex-associated variable penetrance and expressivity [86]. Seizure predisposition is exacerbated by seizure repetition at weekly intervals [87,88] with a seizures-beget-seizures exacerbation that is a characteristic of the forebrain and brainstem seizure circuitry [89].…”

Advances on genetic rat models of epilepsy

“…The rats have an ARS of 9 and the colony was designated the GEPR-9 colony. The GEPR-3 and GEPR-9 rats both show incomplete penetrance and variable expressivity of the underlying genetic predisposition [ 60 ]. Therefore, genetic analysis of quantitative trait loci (QTL) for seizures has not been reported yet.…”