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Published on: September 27, 2015
Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter
P A Leegwater1, G Vermeulen, A A Könst
1Department of Child Neurology, Free University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
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.
Insights
Genetic mutations in EIF2B5 and EIF2B2 cause vanishing white matter (VWM), a progressive inherited brain disease. This discovery links translation initiation factors to VWM, explaining disease progression and stress-related deterioration.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Vanishing white matter (VWM) is a rare, inherited leukoencephalopathy primarily affecting children.
- The disease is characterized by chronic progression and acute neurological decline following stressors like infections or head trauma.
Purpose of the Study:
- To identify the genetic basis of Vanishing White Matter (VWM).
- To investigate the role of translation initiation factor eIF2B in VWM pathogenesis.
Main Methods:
- Genetic analysis of patients diagnosed with VWM.
- Mutation identification in candidate genes EIF2B5 and EIF2B2.
Main Results:
- Identified 16 distinct mutations in EIF2B5 across 29 patients from 23 families.
- Discovered homozygous missense mutations in EIF2B2 in two individuals and additional mutations in three other patients.
- Established mutations in genes encoding subunits of the translation initiation factor eIF2B as the cause of VWM.
Conclusions:
- Mutations in EIF2B5 and EIF2B2 are causative for Vanishing White Matter.
- The role of eIF2B in translation regulation, particularly under stress, provides a molecular explanation for VWM's clinical course.
- This study implicates mutant translation initiation factors in human disease for the first time.
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