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 tish (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 tish brain. Developmental electrographic characterization of the tish rat revealed early-onset 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 tish rat to a deletion in Eml1.

中文翻译：

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Eml1 中的缺失导致 tish 大鼠的双侧皮层下异位。

患有皮质发育畸形 (MCD) 的儿童有患癫痫、发育迟缓、行为障碍和智力障碍的风险。对于这些儿童中的一部分，抗癫痫药物或癫痫手术可能会导致癫痫发作。然而，治疗或治愈其他疾病的选择有限，并且癫痫手术并非适用于所有耐药性癫痫病例。了解 MCD 的遗传和神经生物学机制是阐明新治疗靶点的必要步骤。tish（端脑内部结构异位）大鼠是一种独特的 MCD 模型，具有自发性癫痫发作，但潜在的基因突变仍然未知。DNA 和 RNA 测序显示，包含先前未注释的第一个外显子的缺失显着减少了大脑中的 Eml1 转录本和蛋白质丰度。tish 大鼠的发育电图特征显示自产后第 17 天开始自发棘波放电 (SWD) 爆发早发。双杂交证明突变体 Eml1 等位基因与观察到的发育不良皮层和早发性皮层分离SWD 在单基因常染色体隐性频率中爆发。我们的数据将 tish 大鼠的双侧异位发育不良皮层的发育与 Eml1 中的缺失联系起来。双杂交杂交表明突变的 Eml1 等位基因与观察到的发育不良皮层分离，并且早发性 SWD 以单基因常染色体隐性频率爆发。我们的数据将 tish 大鼠的双侧异位发育不良皮层的发育与 Eml1 中的缺失联系起来。双杂交杂交表明突变的 Eml1 等位基因与观察到的发育不良皮层分离，并且早发性 SWD 以单基因常染色体隐性频率爆发。我们的数据将 tish 大鼠的双侧异位发育不良皮层的发育与 Eml1 中的缺失联系起来。