Submission Details

Autosomal recessive

06/17/2019

The EIF2B2 gene is located on chromosome 14 at 14q24.3 and encodes eukaryotic translation initiation factor 2B subunit beta. EIF2B2 forms a protein complex with four other EIF2B subunits and plays an important role in the initiation of mRNA translation by activating protein synthesis initiation factor 2 through its guanine nucleotide exchange factor activity. EIF2B2 was first reported in relation to leukoencephalopathy with vanishing white matter in 2001 (11704758: Leegwater et al. 2001). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 12 variants, including missense and loss of function variants have been reported in at least eight probands from four publications (11704758: Leegwater et al. 2001; 14566705: van der Knapp et al. 2003; 15054402: Fogli et al. 2004; 21484434: Matsukawa et al. 2011). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Clinical evidence indicates that loss of function is the mechanism of disease. This gene-disease association is supported by the biochemical function of EIF2B2 and other genes in the EIF2B complex are associated with the disease (20301435: van der Knaap et al. 2019). Co-immunoprecipitation experiments demonstrate an interaction between EIF2B2 and all four of the other EIF2B subunits (14993275: Richardson et al. 2004). In vitro functional analyses of patient-identified missense variants suggest loss of function, including disruption of interactions with other subunits and impaired translation (14993275: Richardson et al. 2004). In summary, the EIF2B2 gene is definitively associated with leukoencephalopathy with vanishing white matter.

11704758 15136673 20301435 14993275 14566705 15054402 21484434 30720246 20826436