Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.

ABSTRACT:

Background

Vanishing white matter (VWM) is a leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)-subunit genes (EIF2B1-EIF2B5); 80% are missense mutations. Clinical severity is highly variable, with a strong, unexplained genotype-phenotype correlation.

Materials and methods

With information from a recent natural history study, we severity-graded 97 missense mutations. Using in silico modeling, we created a new human eIF2B model structure, onto which we mapped the missense mutations. Mutated residues were assessed for location in subunits, eIF2B complex, and functional domains, and for information on biochemical activity.

Results

Over 50% of mutations have (ultra-)severe phenotypic effects. About 60% affect the ε-subunit, containing

SUBMITTER: Slynko I 

PROVIDER: S-EPMC8104162 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature