Molecular Characteristics
The EIF2AK1 gene encodes eukaryotic translation initiation factor 2 alpha 1 kinase that phosphorylates the alpha subunit of eukaryotic protein synthesis initiation factor-2 (EIF2S1), which downregulates protein synthesis in response to various stress conditions. EIF2AK1, which is activated by heme deficiency and other stimuli, is a major kinase that phosphorylates EIF2-alpha.
Mutations identified in LEMSPAD syndrome is located in the kinase domain of EIF2AK1.
Mao et al. (2020) transiently overexpressed mutant EIF2AK1 in HEK293T cells and found decreased kinase activity of the mutant protein while wild type protein showed upregulated phosphorylated EIF2S1 (p-EIF2S1). Furthermore, siRNA knockdown of EIF2AK1 significantly reduced p-EIF2S1 levels in both HEK293T and HeLa cell lines. However, the EIF2AK2 siRNAs has no effect on changes in p-EIF2S1 levels, which suggests potential redundancy between the EIF2AK family members in HEK293T and HeLa cells. Mao et al. (2020) concluded that reduced EIF2S1 phosphorylation would interfere with downstream molecular pathways critical for responding to cellular stressors, which may lead to neurologic decompensation and damage. These downstream effects may also impact the EIF2B protein complex, which activates the stress response. Biallelic mutations in related EIF2B genes, including EIF2B1 and EIF2B2, are associated with an overlapping phenotype observed in Vanishing White Matter Disease. Given that EIF2AK1 requires dimerization for the kinase to function, the authors postulated a dominant-negative effect as the pathogenetic mechanism, rather than haploinsufficiency or a gain-of-function effect.
Mutations and pathophysiology
Mutations in EIF2AK1 are postulated to be dominant negative and affect kinase activity of downstream signalling. Mao et al. (2020) reported a single de novo missense variant in EIF2AK1, NM_014413.4; p. (Ile448Val), in an affected individual from Irish, German origin.