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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Malformations of cortical development (MCD) are associated with epilepsy, developmental delays, and intellectual disabilities.
• Effective treatments for MCD beyond seizure control are limited, highlighting the need for understanding underlying mechanisms.
• The tish rat model exhibits spontaneous seizures but its genetic cause was previously unknown.

Purpose of the Study:

• To identify the genetic mutation responsible for MCD and epilepsy in the tish rat.
• To understand the neurobiological mechanisms linking the genetic defect to cortical malformations and seizures.
• To establish the tish rat as a valuable model for studying MCD and developing therapeutic strategies.

Main Methods:

• DNA and RNA sequencing were performed on tish rat brains.
• Developmental electroencephalography was used to characterize seizure activity.
• Dihybrid crosses were conducted to determine the inheritance pattern of the mutation.

Main Results:

• A deletion in a previously unannotated exon of the Eml1 gene was identified, significantly reducing Eml1 transcript and protein levels.
• Spontaneous spike-wave discharge (SWD) bursts were observed starting at postnatal day 17 in tish rats.
• The Eml1 mutation segregated with the dysplastic cortex and early-onset SWD bursts in an autosomal recessive pattern.

Conclusions:

• The study links a deletion in the Eml1 gene to the development of bilateral, heterotopic dysplastic cortex and epilepsy in the tish rat.
• This finding establishes Eml1 as a critical gene in cortical development and epilepsy pathogenesis.
• The tish rat is validated as a genetic model for studying MCD and associated neurological disorders.