Disease relevance of EIF2B5

• Childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter leukoencephalopathy (VWM), is a fatal brain disorder caused by mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for protein synthesis and regulates translation in response to cellular stresses [1].
• Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation [2].
• In contrast, sepsis did not change either the total amount or the phosphorylation state of eIF2alpha or eIF2Bepsilon [3].
• METHODS: Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis [4].
• The human protein hCLE was previously identified by its interaction with the PA subunit of influenza virus polymerase [5].

Psychiatry related information on EIF2B5

• VO2 and HR kinetics during CLE were significantly slower in HTR than in CTRL, whereas, unexpectedly, no significant differences were found for Delta[deoxy(Hb+Mb)] kinetics (mean response time: 21.3 +/- 1.1 vs 20.2 +/- 1.2 s) [6].
• This study examined the relationships between observer ratings of interpersonal style (Chart of Interpersonal Reactions in Closed Living Environment [CIR-CLE]) and the personality disorder scales of the Millon Clinical Multiaxial Inventory (MCMI-I) in a sample of male forensic psychiatric inpatients (N = 104) [7].

High impact information on EIF2B5

• 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 [8].
• EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy [9].
• This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo [10].
• The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1 [10].
• We performed mutagenesis to introduce changes equivalent to 12 human CACH/VWM mutations in three subunits of the equivalent factor from yeast (Saccharomyces cerevisiae) and analyzed effects on cell growth, translation, and gene expression in response to stresses [1].

Biological context of EIF2B5

• The process of localization and identification of the first two genes related to VWM, EIF2B5 and EIF2B2, was facilitated by two founder effects in the Dutch population [11].
• In a fatal infantile leukoencephalopathy, which the authors previously classified as a severe variant of CACH/VWM, a new homozygous missense mutation in the EIF2B5 gene was found [12].
• Sequence analysis of EIF2B5 gene showed that the patient was a double heterozygote, with novel missense mutation CGA-->CAA in codon 269 of exon 6, resulting in the replacement of an arginine residue with glutamine [2].
• Frameshift mutations in genes for eIF2Bepsilon or eIF2Bbeta lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations [13].
• A point mutation in the catalytic domain of eIF2Bepsilon impairs its ability to bind the substrate, while two mutations in eIF2Bbeta actually enhance eIF2 binding [13].

Anatomical context of EIF2B5

• In DM and CLE skin, the number of apoptotic keratinocytes was significantly increased (p=0.008) compared with normal skin [14].
• Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients [15].
• We studied in vitro spontaneous and ultraviolet light (UV)-induced lymphocyte apoptosis in patients with systemic lupus erythematosus (SLE, n = 11), cutaneous lupus erythematosus (CLE, n = 8), and other collagen diseases (n = 6), as well as normal individuals (n = 6) [16].

Associations of EIF2B5 with chemical compounds

• Identification of domains and residues within the epsilon subunit of eukaryotic translation initiation factor 2B (eIF2Bepsilon) required for guanine nucleotide exchange reveals a novel activation function promoted by eIF2B complex formation [17].
• A hydroxyl 12-amino acid peptide derived from the conserved CLE motif of CLV3 promotes cell differentiation, whereas another CLE-derived peptide suppresses the differentiation [18].
• Here we show that Ser(539) of eIF2Bepsilon, which is followed by proline, is phosphorylated specifically by two isoforms of dual-specificity tyrosine phosphorylated and regulated kinase (DYRK2 and DYRK1A), but only weakly or not at all by other 'proline-directed' protein kinases tested [19].
• Cyclolinopeptides CLD and CLE, which contain methionine oxide, were detected in small quantities only [20].

Other interactions of EIF2B5

• Patients without mutations in the EIF2B5 gene were found to be mutated in one of the other genes that encode eIF2B subunits: EIF2B1 to EIF2B4 [21].
• It is reasonably well understood how the initiation of translation is controlled by reversible phosphorylation of the eukaryotic translation initiation factors eIF2alpha, eIF2Bepsilon and eIF4E [22].
• Leukoencephalopathy with vanishing white matter (VWM), also called childhood ataxia with central nervous system hypomyelination (CACH), is an autosomal recessive disease caused by mutations in any of the five genes encoding subunits of the eukaryotic translation initiation factor eIF2B [23].
• The decrease in eIF2Bepsilon content was prevented by treatment of septic rats with TNFBP [24].

Analytical, diagnostic and therapeutic context of EIF2B5

• Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5) [9].
• Accordingly, the expression profiling in hCLE-silenced cells studied by microarray analysis showed that, among the genes that exhibited a differential expression under hCLE silencing, more than 90% were down-regulated [5].
• Here we show that hCLE and different phosphorylated forms of the RNA polymerase II (RNAP II) largest subunit, co-immunoprecipitate and colocalize by confocal microscopy analysis [5].
• METHODS: Twenty male HTR (age 50.4 +/- 2.6 yr; mean +/- SE) and 17 healthy untrained age-matched controls (CTRL) performed an incremental exercise (IE) and a series of constant-load (CLE) moderate-intensity exercise tests on a cycloergometer [6].
• We evaluated 21 normal subjects and 20 patients with LVWM abnormalities revealed by two-dimensional echocardiography [25].

References