A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy

Abstract

The lde/lde rat is characterized by dwarfism, postnatal lethality, male hypogonadism, a high incidence of epilepsy and many vacuoles in the hippocampus and amygdala. We used a candidate approach to identify the gene responsible for the lde phenotype and assessed the susceptibility of lde/lde rats for audiogenic seizures. Following backcross breeding of lethal dwarfism with epilepsy (LDE) to Brown Norway rats, the lde/lde rats with an altered genetic background showed all pleiotropic phenotypes. The lde locus was mapped to a 1.5-Mbp region on rat chromosome 19 that included the latter half of the Wwox gene. Sequencing of the full-length Wwox transcript identified a 13-bp deletion in exon 9 in lde/lde rats. This mutation causes a frame shift, resulting in aberrant amino acid sequences at the C-terminal. Western blotting showed that both the full-length products of the Wwox gene and its isoform were present in normal testes and hippocampi, whereas both products were undetectable in the testes and hippocampi of lde/lde rats. Sound stimulation induced epileptic seizures in 95% of lde/lde rats, with starting as wild running (WR), sometimes progressing to tonic-clonic convulsions. Electroencephalogram (EEG) analysis showed interictal spikes, fast waves during WR and burst of spikes during clonic phases. The Wwox protein is expressed in the central nervous system (CNS), indicating that abnormal neuronal excitability in lde/lde rats may be because of a lack of Wwox function. The lde/lde rat is not only useful for understanding the multiple functions of Wwox but is also a unique model for studying the physiological function of Wwox in CNS.

WWOX, the chromosomal fragile site FRA16D spanning gene: Its role in metabolism and contribution to cancer

“…The neurological symptoms in each of the affected individuals are similar to those observed for the spontaneous rat WWOX mutation indicating likely common pathogenic pathway for these symptoms. The human and rat WWOX mutations also share a lack of noted increase in spontaneous tumours 28,29,31,32 as has been reported for mouse WWOX mutations. [24][25][26][27] Insights into the role of WWOX in metabolism Given the phenotypic consequences of homozygous loss-offunction WWOX mutations in mammals, it is somewhat surprising that loss-of-function WWOX mutations in the D. melanogaster ortholog of WWOX do not exhibit a phenotype.…”

“…[24][25][26][27] A spontaneous WWOX mutant rat does not exhibit higher incidence of tumors. 28,29 Rodent WWOX mutants typically exhibit metabolic disorders leading to early death (which may preclude development of some tumors) limiting the utility of rodent models in understanding WWOX protein function. [24][25][26][27][28][29] While these rodent studies have provided some insight into the biological role for WWOX, there is still clearly a need to understand the molecular processes and pathways in which WWOX participates; particularly how WWOX contributes to metabolism and how this altered metabolism can contribute, at least in certain circumstances, to cancer.…”

Introduction to a Thematic Issue for WWOX

“…23 Similar observation is shown in the Ide/Ide rat. 24 The underlying mechanisms remain to be established. (2) WWOX binds viral proteins and is likely to control viral proliferation.…”

“…23 In Ide/Ide rat, the Wwox gene has been shown to possess a 13-bp deletion in exon 9 that causes the rats to suffer dwarfism, postnatal lethality, male hypogonadism, and a high incidence of epilepsy and many vacuoles in the hippocampus and amygdala. 24 Under the loss of WWOX protein, no spontaneous tumor formation was shown. In stark contrast, functional deficiency of WWOX in Drosophila does not generate the disease phenotypes in the neural system.…”

The fragile site WWOX gene and the developing brain

“…Experimental studies: Mutation of the WWOX gene and audiogenic seizures in rats with epilepsy and lethal dwarfism Suzuki et al 13 analyzed a spontaneous rat mutant (Ide/Ide) and reported a phenotype characterized by dwarfism, hypogonadism, epilepsy, and postnatal lethality. Brain pathology showed extracellular vacuoles in the hippocampus and amygdala.…”