SLC1A2, encoding excitatory amino acid transporter 2 (EAAT2, GLT-1), was first reported in relation to autosomal dominant early infantile epileptic encephalopathy in 2016 (Epi4K Consortium., PMID: 27476654). Only four de novo missense variants, two of which result in an identical Gly82Arg protein change, have been reported in humans. A single mild recessive case with a homozygous splicing variant has been reported in the literature, however given no other cases and a lack of functional studies they have not been evaluated in this curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in six probands in four separate publications (PMIDs: 23934111, 27476654, 28777935, 30937933). Each of these cases stem from a de novo missense variant that affects one of the transmembrane helices in the trimerization domain. The mechanism for disease is a heterozygous dominant negative effect, with missense variants disrupting the monomeric and trimeric structures of the protein causing a reduction of glutamate transport activity by both WT and mutant protein (Stergachis et al., PMID: 30937933). This gene-disease association, in addition to the integral biochemical function of being a CNS glutamate transporter, is also supported by multiple mouse models. A knock-out mouse model showed significantly increased fatality rates due to epileptic seizure activity and susceptibility to brain injury, recapitulating the phenotypes of the human disorder but without the dominant negative mechanism. Similarly, a conditional knock-out of GLT-1 in mouse astrocytes and neurons demonstrates that astrocytic GLT-1 protects against seizures and epilepsy while neuronal GLT-1 is integral to glutamate uptake. This clearly shows that alteration of protein expression can have significant impacts on overall function. In summary, SLC1A2 is definitively associated with autosomal dominant early infantile epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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