Vanishing white matter

Autor: Eline M.C. Hamilton, Stephanie Nguyen, Chris de Graaf, Iwan J. P. de Esch, Christopher G. Proud, John B. Bruning, Lisanne E. Wisse, Marjo S. van der Knaap, Inna Slynko, Truus Em Abbink
Přispěvatelé: Medicinal chemistry, Chemistry and Pharmaceutical Sciences, AIMMS, Functional Genomics, Neurology, Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Molecular Genetics & Genomic Medicine
Molecular Genetics & Genomic Medicine, Vol 9, Iss 3, Pp n/a-n/a (2021)
Molecular Genetics and Genomic Medicine, 9(3):e1593, 1-15. John Wiley and Sons Inc.
Molecular Genetics and Genomic Medicine, 9(3):e1593. John Wiley and Sons Inc.
Slynko, I, Nguyen, S, Hamilton, E M C, Wisse, L E, de Esch, I J P, de Graaf, C, Bruning, J B, Proud, C G, Abbink, T E M & van der Knaap, M S 2021, ' Vanishing white matter : Eukaryotic initiation factor 2B model and the impact of missense mutations ', Molecular Genetics and Genomic Medicine, vol. 9, no. 3, e1593, pp. 1-15 . https://doi.org/10.1002/mgg3.1593
Slynko, I, Nguyen, S, Hamilton, E M C, Wisse, L E, de Esch, I J P, de Graaf, C, Bruning, J B, Proud, C G, Abbink, T E M & van der Knaap, M S 2021, ' Vanishing white matter : Eukaryotic initiation factor 2B model and the impact of missense mutations ', Molecular Genetics and Genomic Medicine, vol. 9, no. 3, e1593 . https://doi.org/10.1002/mgg3.1593
ISSN: 2324-9269
DOI: 10.1002/mgg3.1593
Popis: 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.
Vanishing white matter (VWM) is a clinically highly variable leukodystrophy, caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B)‐subunit genes, mostly missense mutations. To gain insight into the strong genotype‐phenotype correlation, we severity‐graded 97 missense mutations using information from a clinical natural history study, created a new human eIF2B model structure by in silico modeling, and assessed mutated residues for location in subunits, eIF2B complex, and functional domains, and for information on biochemical activity. We demonstrated that mutations associated with (ultra‐)severe disease mostly affect amino acids with pivotal roles in complex formation and eIF2B function, while mutations on the external eIf2B surface are mostly associated with mild phenotypes, probably because of minor functional effects. Therapies for VWM are emerging and reliable mutation‐based phenotype prediction is required for propensity score matching for trials and individualized therapy decisions.
Databáze: OpenAIRE
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