A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat

NEUROBIOLOGY OF DISEASE

卷:140

Article

Grosenbaugh, Denise K.¹  Joshi, Suchitra¹  Fitzgerald, Mark P.⁴  Lee, Kevin S.^4,5,6  Wagley, Pravin K.¹  Koeppel, Alexander F.⁸  Turner, Stephen D.⁸  McConnell, Michael J.^3,4,6,7  Goodkin, Howard P.^1,2 

[1] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA

[2] Univ Virginia, Sch Med, Dept Pediat, Charlottesville, VA 22908 USA

[3] Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA

[4] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA

[5] Univ Virginia, Sch Med, Dept Neurosurg, Charlottesville, VA 22908 USA

[6] Univ Virginia, Sch Med, Ctr Brain Immunol & Glia, Charlottesville, VA 22908 USA

[7] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

[8] Univ Virginia, Sch Med, Ctr Publ Hlth Sci, Charlottesville, VA 22908 USA

关键词: Dysplasia;    Epilepsy;    EEG;   

DOI  :  10.1016/j.nbd.2020.104836

来源: Elsevier

【 摘 要 】

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The fish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the fish brain. Developmental electrographic characterization of the fish rat revealed earlyonset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the fish rat to a deletion in Eml1.