Unraveling genetic modifiers in the gria4 mouse model of absence epilepsy.
Unraveling genetic modifiers in the gria4 mouse model of absence epilepsy.
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DOI：
10.1371/journal.pgen.1004454
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发表时间：
2014-07
期刊：
影响因子：
4.5
通讯作者：
Letts VA
中科院分区：
文献类型：
--
作者：
Frankel WN;Mahaffey CL;McGarr TC;Beyer BJ;Letts VA
Absence epilepsy (AE) is a common type of genetic generalized epilepsy (GGE), particularly in children. AE and GGE are complex genetic diseases with few causal variants identified to date. Gria4 deficient mice provide a model of AE, one for which the common laboratory inbred strain C3H/HeJ (HeJ) harbors a natural IAP retrotransposon insertion in Gria4 that reduces its expression 8-fold. Between C3H and non-seizing strains such as C57BL/6, genetic modifiers alter disease severity. Even C3H substrains have surprising variation in the duration and incidence of spike-wave discharges (SWD), the characteristic electroencephalographic feature of absence seizures. Here we discovered extensive IAP retrotransposition in the C3H substrain, and identified a HeJ-private IAP in the Pcnxl2 gene, which encodes a putative multi-transmembrane protein of unknown function, resulting in decreased expression. By creating new Pcnxl2 frameshift alleles using TALEN mutagenesis, we show that Pcnxl2 deficiency is responsible for mitigating the seizure phenotype – making Pcnxl2 the first known modifier gene for absence seizures in any species. This finding gave us a handle on genetic complexity between strains, directing us to use another C3H substrain to map additional modifiers including validation of a Chr 15 locus that profoundly affects the severity of SWD episodes. Together these new findings expand our knowledge of how natural variation modulates seizures, and highlights the feasibility of characterizing and validating modifiers in mouse strains and substrains in the post-genome sequence era. Absence seizures - also known as “petit-mal” - define a common form of epilepsy most prevalent in children, but also seen at other ages, and in related diseases such as juvenile myoclonic epilepsy. Absence seizures cause brief periods of unconsciousness, and are accompanied by characteristic abnormal brain waves called “spike-wave discharges” (SWD) due to their appearance in the electroencephalogram (EEG). Although few genes are known for human absence seizures, perhaps because the underlying genetics are complex, several laboratory rodent models exist, including one caused by mutation of a gene called Gria4. While studying Gria4, we noticed that a mouse strain called C3H can suppress or enhance the frequency and severity of Gria4-associated SWD in a perplexing manner; such effects are generally attributed to “modifier” genes. Here we identify a novel modifier – called “pecanex-like 2”, or Pcnxl2 for short – that reduces the severity of SWD in the C3H substrain in which the Gria4 mutation originally arose. This finding directed us to use of related substrains to locate additional modifiers, one of which has an even more profound effect on SWD episodes. Modifier genes, nature's way of controlling seizure severity, are promising targets for better understanding seizure mechanisms and potential new therapies in the future.
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