Molecular Characteristics
The EIF2AK2 gene encodes a serine/threonine kinase that acquires enzymatic activity following autophosphorylation, a process mediated by double-stranded RNA (dsRNA) that is associated with viral infections. Activation of EIF2AK2 allows the kinase to phosphorylate its natural substrate, the alpha subunit of eukaryotic protein synthesis initiation factor-2 (EIF2-alpha), leading to the inhibition of protein synthesis. Members of the EIF2AK gene family inhibit protein synthesis in response to physiologic stress conditions by regulating the cytoprotective integrated stress response (ISR). EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. The mutations identified in LEUDEN syndrome are spread throughout the gene, but most occurred in the kinase or double-stranded RNA-binding motif (DSRM) domains of EIF2AK2.
Studies of fibroblasts derived from 3 patients by Mao et al. (2020) showed that the mutant proteins were stably expressed, but had decreased kinase activity toward EIF2S1 compared to wildtype. Patient cells also showed decreased levels of the downstream regulator ATF4 and 2 of the cell lines showed impaired response to induced physiological stress. 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 EIF2AK2 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 EIF2AK2 are postulated to be dominant negative and affect kinase activity of downstream signaling. Mao et al. (2020) reported de novo EIF2AK2 (NM_002759.3) missense variants in 8 affected individuals from unrelated families leading to developmental delay, leukoencephalopathy, and neurologic decompensation. The summary of variants identified so far:
– c.31A>C; p.(Met11Leu) affecting an individual from German, Mexican and Spanish origin
– c.398A>T; p.(Tyr133Phe) affecting an individual from Chinese origin
– c.973G>A; p.(Gly325Ser) affecting an individual from European origin
– c.1382C>G; p.(Ser461Cys) affecting an individual from European origin
– c.326C>T; p.(Ala109Val) affecting an individual from Moroccan, Kuwaiti origin
– c.325G>T; p.(Ala109ser) affecting an individual from European origin
– c.95A>G; p.(Asn32Ser) affecting an individual from European origin
– c.290C>T; p.(Ser97Phe) affecting an individual from German, Irish, Apache, Cherokee origin