Sodium-Dependent Plasma Membrane Citrate Transporter (SLC13A5) Missense Mutations Cause Epileptiform Activity and Status Epilepticus in Mouse Mutants
Abstract number :
1.065
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2021
Submission ID :
1826596
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:54 AM
Authors :
Kelvin De Leon, BA - Brown University; Stephen Helfand - Brown University; Judy Liu - Brown University
Rationale: Mutations in the SLC13A5 gene, which encodes a plasma membrane citrate transporter, result in a newly diagnosed form of genetic epilepsy termed early infantile epileptic encephalopathy, which is characterized by multi-focal seizures in neonates. These infants subsequently develop cognitive and behavioral deficits. Human genetics has identified both commonly occurring missense and deletion mutations, but it is not known how distinct genetic mutations affect disease presentation and seizure severity.
Methods: We are addressing this question by characterizing an array of SLC13A5 mutant mouse models carrying: i) ablation of its endogenous murine Slc13a5 gene (knockout), ii) the most common patient mutation, the G222R point mutation (equivalent to the human mutation G219R), and iii) the second most common patient mutation, the T230M (equivalent to the human mutation T227M).
Results: Our preliminary data demonstrates that homozygous Slc13a5 knockout, which shows abnormal neurotransmitter levels, and heterozygous T230M+/- mutant, both demonstrate mild epileptiform electroencephalogram (EEG) profiles, while heterozygous G222R+/- point mutation and homozygous G222R-/- have more severe epileptiform activity. Strikingly however, severe status epilepticus is observed only in heterozygous G219R+/- mutant mice, which is accompanied by evidence of brain tissue damage detected by immunohistochemistry. Unlike the wild-type recombinant human Slc13a5 and T227M mutant, the G219R mutant protein fails to localize to the plasma membrane and remains in the cytoplasm in HEK293 cells. Co-expression of G219R mutant together with its wild-type counterpart additionally prevents membrane localization of the wild-type protein.
Conclusions: These results are consistent with our interpretation that SLC13A5 loss of function causes epilepsy via altered neurotransmitter levels, and that specific missense mutations may acquire dominant gain-of-function effects which exacerbate neuronal hyperexcitability.
Funding: Please list any funding that was received in support of this abstract.: None.
Basic Mechanisms