ArticleMolecular genetics & genomic medicine2021
Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.
Article in Molecular genetics & genomic medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Termination of the integrated stress response.Science (New York, N.Y.) · 2026Article
- Consensus-Based Expert Recommendations for Diagnosis and Clinical Management of Vanishing White Matter.Neurology · 2025Review
- Chronic integrated stress response causes dysregulated cholesterol synthesis in white matter disease.JCI insight · 2025Article
- Quantitative MRI distinguishes different leukodystrophies and correlates with clinical measures.European radiology · 2025Article
- "Case report": Whole-exome sequencing reveals compound heterozygous variants in theFrontiers in genetics · 2025Article
- Case Report: New genetic variant and widely different phenotypes observed in twins with Vanishing White Matter disease.Frontiers in pediatrics · 2025Article
- In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Screening of premature ovarian insufficiency associated genes in Hungarian patients with next generation sequencing.BMC medical genomics · 2024Article
- Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.BMC neurology · 2023Article
- Genetic diversity and signatures of selection in four indigenous horse breeds of Iran.Heredity · 2023Article
- Vector enabled CRISPR gene editing - A revolutionary strategy for targeting the diversity of brain pathologies.Coordination chemistry reviews · 2023Article
- From Translation to Treatment.Faculty reviews · 2023Review
- Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2022Review
- Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1.Annals of clinical and translational neurology · 2022Article
- Therapy Trial Design in Vanishing White Matter: An Expert Consortium Opinion.Neurology. Genetics · 2022Review
- Association Between Late-Onset Leukoencephalopathy With Vanishing White Matter and Compound Heterozygous EIF2B5 Gene Mutations: A Case Report and Review of the Literature.Frontiers in neurology · 2022Article
- Correlation Between Genotype and Age of Onset in Leukoencephalopathy With Vanishing White Matter.Frontiers in genetics · 2021Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundVanishing 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
methodsWith 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.
resultsOver 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.
conclusionMutations 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.
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