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

Inna Slynko, Stephanie Nguyen, Eline M C Hamilton, Lisanne E Wisse, Iwan J P de Esch, Chris de Graaf, John B Bruning, Christopher G Proud, Truus E M Abbink, Marjo S van der Knaap

Research output: Contribution to JournalArticleAcademicpeer-review

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 the catalytic domain, mostly with (ultra-)severe effects. About 55% affect subunit cores, with variable clinical severity. About 36% affect subunit interfaces, mostly with severe effects. Very few mutations occur on the external eIf2B surface, perhaps because they have minor functional effects and are tolerated. One external surface mutation affects eIF2B-substrate interaction and is associated with ultra-severe phenotype.

CONCLUSION: Mutations that lead to (ultra-)severe disease mostly affect amino acids with pivotal roles in complex formation and function of eIF2B. Therapies for VWM are emerging and reliable mutation-based phenotype prediction is required for propensity score matching for trials and in the future for individualized therapy decisions.

Original languageEnglish
Article numbere1593
Pages (from-to)1-15
Number of pages15
JournalMolecular Genetics and Genomic Medicine
Volume9
Issue number3
Early online date12 Jan 2021
DOIs
Publication statusPublished - Mar 2021

Bibliographical note

© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Keywords

  • Eukaryotic Initiation Factor-2B/genetics
  • Humans
  • Leukoencephalopathies/genetics
  • Molecular Dynamics Simulation
  • Mutation, Missense
  • Phenotype
  • Protein Domains

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