Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter

Abstract

Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.

Axonal abnormalities in vanishing white matter

“…VWM is caused by mutations in the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (eIF2B), EIF2B1 through EIF2B5 7, 8. eIF2B is an enzyme complex essential for translation of mRNAs into proteins and central in downregulating the rate of translation under different stress conditions 9.…”

Natural History of Vanishing White Matter

“…It is caused by recessive mutations in any of the genes EIF2B1–5. 5, 6 Patients typically have normal early development, followed by chronic neurological deterioration and additionally stress‐provoked episodes of rapid decline 2. No curative treatment is available 7.…”

Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease

“…To initiate the next round of translations, eIF2-bound GDP must be replaced by GTP; in this process, eIF2B subunits catalyze the exchange of GDP with GTP. 16 The pathogenic mechanisms of VWM due to eIF2B gene defects are far from well understood; the aberrant translation of some protein with upstream open reading frames in mRNA, such as activating transcription factor (ATF) 4, and activation of unfolded-protein response (UPR) in ER are believed to be involved. [12][13][14][15] eIF2B is a complex of five subunits.…”

“…Mutations in EIF2B1-5, encoding the five subunits of eukaryotic translation initiation factor (eIF2B a, b, g, d and e), respectively, were found in VWM patients. 4,5 eIF2B, along with some other eIFs, plays key roles in the initiation of protein translation in all eukaryotic cells. Since 2001, more than 120 mutations in EIF2B1-5 have been identified.…”