scholarly journals Comparative Proteome Research in a Zebrafish Model for Vanishing White Matter Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2707
Author(s):  
Doeun Kim ◽  
Yu-Ri Lee ◽  
Tae-Ik Choi ◽  
Se-Hee Kim ◽  
Hoon-Chul Kang ◽  
...  
Keyword(s):  
White Matter ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Early Death ◽  
Mrna Levels ◽  
Zebrafish Model ◽  
Quantitative Proteomic Analysis ◽  
Eukaryotic Translation ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Vanishing white matter (VWM) disease is a genetic leukodystrophy leading to severe neurological disease and early death. VWM is caused by bi-allelic mutations in any of the five genes encoding the subunits of the eukaryotic translation factor 2B (EIF2B). Previous studies have attempted to investigate the molecular mechanism of VWN by constructing models for each subunit of EIF2B that causes VWM disease. The underlying molecular mechanisms of the way in which mutations in EIF2B3 result in VWM are largely unknown. Based on our recent results, we generated an eif2b3 knockout (eif2b3−/−) zebrafish model and performed quantitative proteomic analysis between the wild-type (WT) and eif2b3−/− zebrafish, and identified 25 differentially expressed proteins. Four proteins were significantly upregulated, and 21 proteins were significantly downregulated in eif2b3−/− zebrafish compared to WT. Lon protease and the neutral amino acid transporter SLC1A4 were significantly increased in eif2b3−/− zebrafish, and crystallin proteins were significantly decreased. The differential expression of proteins was confirmed by the evaluation of mRNA levels in eif2b3−/− zebrafish, using whole-mount in situ hybridization analysis. This study identified proteins which candidates as key regulators of the progression of VWN disease, using quantitative proteomic analysis in the first EIF2B3 animal model of VWN disease.

Eif2b3 mutants recapitulate phenotypes of Vanishing White Matter Disease and validate novel disease alleles in zebrafish

2021 ◽  
Author(s):  
Yu-Ri Lee ◽  
Se Hee Kim ◽  
Afif Ben-Mahmoud ◽  
Oc-Hee Kim ◽  
Tae-Ik Choi ◽  
...  
Keyword(s):  
White Matter ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Vegf Receptor ◽  
Zebrafish Model ◽  
Eukaryotic Translation ◽  
Expression Of Genes ◽  
Novel Variant ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Abstract Leukodystrophy with Vanishing White Matter (VWM), also called Childhood Ataxia with Central Nervous System Hypomyelination (CACH), is caused by mutations in the subunits of the eukaryotic translation initiation factor, EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. However, little is known regarding the underlying pathogenetic mechanisms, and there is no curative treatment for VWM. In this study, we established the first EIF2B3 animal model for VWM disease in vertebrates by CRISPR mutagenesis of the highly conserved zebrafish ortholog eif2b3. Using CRISPR, we generated two mutant alleles in zebrafish eif2b3, 10- and 16-bp deletions, respectively. The eif2b3 mutants showed defects in myelin development and glial cell differentiation, and increased expression of genes in the induced stress response pathway. Interestingly, we also found ectopic angiogenesis and increased VEGF expression. Ectopic angiogenesis in the eif2b3 mutants was reduced by administration of VEGF receptor inhibitor SU5416. Using the eif2b3 mutant zebrafish model together with in silico protein modeling analysis, we demonstrated the pathogenicity of 18 reported mutations in EIF2B3, as well as of a novel variant identified in a 19-month-old female patient: c.503 T > C (p.Leu168Pro). In summary, our zebrafish mutant model of eif2b3 provides novel insights into VWM pathogenesis and offers rapid functional analysis of human EIF2B3 gene variants.

scholarly journals Vanishing White Matter Disease in a Spanish Population

2014 ◽  
Vol 6 ◽  
pp. JCNSD.S13540 ◽  
Author(s):  
Eulàlia Turón-Viñas ◽  
Mercè Pineda ◽  
Victòria Cusí ◽  
Eduardo López-Laso ◽  
Rebeca Losada Del Pozo ◽  
...  
Keyword(s):  
White Matter ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Genes Encoding ◽  
Eukaryotic Translation Initiation ◽  
Severe Ataxia ◽  
Vanishing White Matter Disease ◽  
Chronic Course ◽  
Vanishing White Matter

Vanishing white matter (VWM) leukoencephalopathy is one of the most prevalent hereditary white matter diseases. It has been associated with mutations in genes encoding eukaryotic translation initiation factor ( eIF2B). We have compiled a list of all the patients diagnosed with VWM in Spain; we found 21 children. The first clinical manifestation in all of them was spasticity, with severe ataxia in six patients, hemiparesis in one child, and dystonic movements in another. They suffered from progressive cognitive deterioration and nine of them had epilepsy too. In four children, we observed optic atrophy and three also had progressive macrocephaly, which is not common in VWM disease. The first two cases were diagnosed before the 1980s. Therefore, they were diagnosed by necropsy studies. The last 16 patients were diagnosed according to genetics: we found mutations in the genes eIF2B5 (13 cases), eIF2B3 (2 cases), and eIF2B4 (1 case). In our report, the second mutation in frequency was c.318A>T; patients with this mutation all followed a slow chronic course, both in homozygous and heterozygous states. Previously, there were no other reports to confirm this fact. We also found some mutations not described in previous reports: c.1090C>T in eIF2B4, c.314A>G in eIF2B5, and c.877C>T in eIF2B5.

scholarly journals A case report of leukoencephalopathy with vanishing white matter disease

2020 ◽  
Vol 7 (6) ◽  
pp. 1438
Author(s):  
Bommidi Navya ◽  
Vamshi Krishna Kondle ◽  
Komal Uppal
Keyword(s):  
White Matter ◽  
Specific Treatment ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
White Matter Disease ◽  
Eukaryotic Translation ◽  
Genes Encoding ◽  
Eukaryotic Translation Initiation ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter

Vanishing white matter disease (VWM) is one of the most prevalent inherited childhood leucoencephalopathies. Childhood ataxia and diffuse central nervous system hypomyelination are the common findings. The disease is characterized by chronic progressive and episodic deterioration with ataxia, spasticity and optic atrophy. VWM is caused by mutation in any of the five genes encoding the subunits of eukaryotic translation initiation factor eIF2B. The disease has an autosomal recessive mode of inheritance. The cause of the disease is unknown. Authors are reporting an 8 year old male child presented with complaint of difficulty while walking since one month and history viral fever was present one month back. MRI revealed bilateral symmetrical periventricular T2 hyperintensities with T1 hypointensities. Perivenular sparing was seen and molecular analysis shown eIF2B4 mutations confirmation of vanishing white matter disease. No specific treatment is available and advised to avoid stress and triggers.

scholarly journals Vanishing White Matter Disease Expression of Truncated EIF2B5 Activates Induced Stress Response

2020 ◽  
Author(s):  
Matthew D. Keefe ◽  
Haille E. Soderholm ◽  
Hung-Yu Shih ◽  
Tamara J. Stevenson ◽  
Kathryn A. Glaittli ◽  
...  
Keyword(s):  
White Matter ◽  
Motor Behavior ◽  
Somatic Growth ◽  
Initiation Factor ◽  
White Matter Disease ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Vanishing White Matter Disease ◽  
Development And Validation ◽  
Vanishing White Matter

AbstractVanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, impaired myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

scholarly journals Poor Cerebral Inflammatory Response in eIF2B Knock-In Mice: Implications for the Aetiology of Vanishing White Matter Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e46715 ◽  
Author(s):  
Yuval Cabilly ◽  
Mali Barbi ◽  
Michal Geva ◽  
Liraz Marom ◽  
David Chetrit ◽  
...  
Keyword(s):  
White Matter ◽  
Inflammatory Response ◽  
White Matter Disease ◽  
Vanishing White Matter Disease ◽  
Vanishing White Matter
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