Journal
MOLECULAR GENETICS & GENOMIC MEDICINE
Volume 9, Issue 3, Pages -Publisher
WILEY
DOI: 10.1002/mgg3.1593
Keywords
eIF2B mutations; genotype-phenotype correlation; vanishing white matter; 3D model structure
Categories
Funding
- ZonMw [91211005]
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) [TOPPUNT 718.014.002]
Ask authors/readers for more resources
This study analyzed 97 missense mutations in vanishing white matter disease (VWM) and found that over 50% of mutations have (ultra-)severe phenotypic effects. Approximately 60% of mutations affect the ε-subunit containing the catalytic domain, while about 36% affect subunit interfaces, mostly with severe effects.
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 epsilon-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available