Collaborative Cross Mouse Population Reveals Novel Genetic Linkage of Sudden Unexpected Death in Epilepsy
Abstract number :
1.059
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2021
Submission ID :
1825514
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:43 AM
Authors :
Bin Gu, PhD - Ohio State University; James Xenakis, PhD - The University of North Carolina, Chapel Hill; John Shorter, PhD - The University of North Carolina, Chapel Hill; Wei Tang, PhD - The University of North Carolina at Chapel Hill; Timothy Bell, PhD - The University of North Carolina at Chapel Hill; Yiyun Pan, B.S. - The University of North Carolina, Chapel Hill; Noah Miller, B.S. - The University of North Carolina, Chapel Hill; Naomi Johnson, undergraduate - the University of North Carolina, Chapel Hill; Wenjing Xu, PhD - Ohio State University; Darla Miller, PhD - The University of North Carolina at Chapel Hill; Rachel Lynch, PhD - The University of North Carolina at Chapel Hill; Benjamin Philpot, PhD - the University of North Carolina, Chapel Hill; Fernando Pardo Manuel de Villena, PhD - The University of North Carolina at Chapel Hill
Rationale: Sudden unexpected death in epilepsy (SUDEP) is the most catastrophic yet overlooked complication of epilepsy. However, there is no method to predict or prevent SUDEP. Animal models play a fundamental role in understanding the genetic basis and pathophysiology of SUDEP and identifying therapeutic interventions. However, existing animal models of SUDEP do not reflect the high level of genetic diversity found in the human population. The Collaborative Cross (CC) population is an innovative recombinant inbred panel of mice (Nat Genet, 2004 36:1133-1137). The CC mice offer large genetic and phenotypic diversity, as well as powerful genomic tools including whole genome sequence to facilitate identification of candidate genes and candidate variants.
Methods: We previously identified 4 CC strains (CC003, CC008, CC009, and CC029) who succumbed to death immediately following flurothyl-induced seizure (Epilepsia, 2020 61:2010-2021). In this study, we first characterized the cardiac function of these pro-SUDEP CC mice using electrocardiography and echocardiography. To identify the regions on the mouse genome that control the trait of SUDEP, we generated an F2 mapping population by reciprocal intercrossing SUDEP susceptible and resistant CC strains. We then tested their SUDEP sensitivity using the flurothyl kindling paradigm and genotyped them using Mini Mouse Universal Genotyping Array. We finally performed quantitative trait locus (QTL) mapping to reveal the QTL that controls SUDEP risk/resilience.
Results: 1) Among 4 pro-SUDEP CC strains, we found CC009 and CC029 exhibited prolonged QT interval, a risk factor of cardiac sudden death. 2) We generated 353 F2 mice from SUDEP susceptible and resistant CC strains and tested them using flurothyl kindling model. Out of 353 F2 mice, 21 died on day 1 (5.9%) and 75 (21.2%) died by the completion of 8-day flurothyl kindling. Using QTL mapping, we identified a single significant locus (CC SUDEP susceptibility, Ccss) on chromosome 9 that controls the traits of SUDEP. 3) We combined whole-genome sequencing and gene expression in various brain regions of parental CC strains to pinpoint biologically plausible candidate genes and variants associated with SUDEP sensitivity.
Conclusions: The CC provides powerful resources for studying complex features of seizures and for identifying genes associated with SUDEP. These data enable the identification of novel molecular targets of SUDEP and finally facilitate the development of therapeutic interventions of SUDEP.
Funding: Please list any funding that was received in support of this abstract.: Taking Flight Award, Citizens United for Research in Epilepsy.
Basic Mechanisms