Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2B5
Cytogenetic location: 3q27.1 Genomic coordinates (GRCh38) : 3:184,135,358-184,145,311 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.1 | Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure | 620315 | Autosomal recessive | 3 |
The EIF2B5 gene encodes a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see 603907). EIF2B catalyzes the exchange of GDP for GTP (summary by Asuru et al., 1996).
Asuru et al. (1996) isolated a rabbit reticulocyte cDNA encoding the epsilon subunit of eIF2B. The predicted 721-amino acid protein migrates at approximately 84 kD by SDS-PAGE. The authors stated that the N-terminal region of eIF2B-epsilon contains a putative nucleotide-binding domain that may be directly involved in nucleotide exchange. By screening a human histiocytic lymphoma cell line library with the rabbit cDNA, Asuru et al. (1996) identified a partial cDNA encoding human eIF2B-epsilon. The deduced partial human protein contains 641 amino acids and is 90% identical to rabbit eIF2B-epsilon.
Leegwater et al. (2001) determined that the EIF2B5 gene contains 16 exons.
Gross (2015) mapped the EIF2B5 gene to chromosome 3q27.1 based on an alignment of the EIF2B5 sequence (GenBank BC013590) with the genomic sequence (GRCh38).
Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (603896) with homozygous or compound heterozygous mutations in EIF2B2 (606454), EIF2B3 (606273), EIF2B4 (606687), and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease.
In cell cultures from the brain of an individual with VWM who had compound heterozygosity for mutations in EIF2B5 (T91A, 603945.0001 and W628R, 603945.0002), Dietrich et al. (2005) observed prompt development of normal-appearing oligodendrocytes despite the extensive demyelination seen in the patient. However, few glial fibrillary acidic protein (GFAP; 137780)-expressing astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP-expressing astrocytes, and RNA-interference targeting of EIF2B5 severely compromised the induction of GFAP-expressing cells from normal human glial progenitors. Dietrich et al. (2005) suggested that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.
Cryoelectron Microscopy
Integrated stress response inhibitor (ISRIB) is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, Tsai et al. (2018) solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. Tsai et al. (2018) concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.
Individuals with leukoencephalopathy with vanishing white matter (VWM5; 620315) initially develop normally or close to normally. Neurologic deterioration usually begins in late infancy or early childhood, but juvenile- and adult-onset cases have been described. Mild and severe cases have been observed, even within families. The neurologic signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy, and relatively preserved mental abilities. Disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Head trauma leads only to motor deterioration, whereas infections with fever may end in coma. Death occurs after a variable period of several years to a few decades, usually following an episode of fever and coma. MRI is diagnostic and shows a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage. Both MRI and magnetic resonance spectroscopy indicate that, with time, an increasing amount of the abnormal white matter vanishes and is replaced by cerebrospinal fluid. The mode of inheritance is autosomal recessive. Leegwater et al. (1999) mapped the disorder to 3q27 and Leegwater et al. (2001) narrowed the location to a region containing a total of 25 genes and STSs. One of these genes, EIF2B5, was found to contain 16 different mutations in 29 patients from 23 families (e.g., 603945.0001-603945.0005).
Cree leukoencephalopathy (CLE) is a rapidly fatal infantile autosomal recessive leukodystrophy observed in the indigenous Cree and Chippewayan populations in northern Quebec and Manitoba. Fogli et al. (2002) found the typical foamy cells with the oligodendroglial phenotype described in CACH/VWM in the brains of individuals with CLE. They studied the EIF2B5 gene in 3 patients of 2 Cree families and identified a homozygous missense mutation (R195H; 603945.0005).
In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter, Fogli et al. (2002) identified a homozygous missense mutation in the EIF2B5 gene (L309V; 603945.0006).
Fogli et al. (2003) identified mutations in the EIF2B2, EIF2B4 (606687), and EIF2B5 genes (e.g., R195C; 603945.0007) in patients with VWM with ovarian failure, which they referred to as ovarioleukodystrophy.
In a Japanese woman with adult-onset VWM5, Ohtake et al. (2004) identified homozygosity for a missense mutation in the EIF2B5 gene (T182M; 603945.0008).
Passemard et al. (2007) reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (603945.0009-603945.0011).
Three novel missense mutations in the EIF2B5 gene were identified by van der Knaap et al. (2003).
Fogli et al. (2004) found that 42 of 68 (62%) VWM families had mutations in the EIF2B5 gene; 71% of those had the R113H mutation (603945.0004).
In 6 of 11 unrelated Chinese patients with VWM disease, Wu et al. (2009) identified homozygous or compound heterozygous mutations in the EIF2B5 gene, including 3 novel missense mutations and a deletion.
In a 53-year-old Japanese man with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B5 gene (D270H; 603945.0012).
In addition to mutations in the EIF2B5 gene, Leegwater et al. (2001) found mutations in the gene encoding the beta subunit of eIF2B (EIF2B2; 606454) in 4 other patients. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, Leegwater et al. (2001) suggested that this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. Mutations in a gene for a modulator of eIF2-eIF2B activity, EIF2AK3 (604032), cause Wolcott-Rallison syndrome (226980). This syndrome is characterized by the malfunctioning of multiple organs and tissues. EIF2AK3 encodes a kinase that specifically phosphorylates the alpha-subunit of eIF2, which suggests that the syndrome is caused by a failure to downregulate translation under stress conditions that would normally enhance eIF2AK3 activity. EIF2AK3 is probably not essential for survival, as patients homozygous for nonsense mutations at this locus have been identified. In VWM only the brain is affected.
Van der Lei et al. (2010) identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with leukoencephalopathy with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (603945.0004), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (603945.0001), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. Van der Lei et al. (2010) concluded that the clinical phenotype in VWM is influenced by the combination of both mutations.
In a 53-year-old Japanese man with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B5 gene (D270H; 603945.0012). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
In 12 individuals with leukoencephalopathy with vanishing white matter (VWM5; 620315) from 9 families who shared a haplotype designated 'EN' because a large number of their ancestors lived in a rural region in the eastern part of the Netherlands, Leegwater et al. (2001) found homozygosity for a 271A-G transition in exon 2 of the EIF2B5 gene, resulting in an amino acid change of threonine to alanine at codon 91 (T91A).
In a patient with leukoencephalopathy with vanishing white matter (VWM5; 620315), Leegwater et al. (2001) found an c.1882T-C transition in exon 14 of the EIF2B5 gene, resulting in a trp628-to-arg (W628R) amino acid substitution. The exon 14 mutation was in compound heterozygous state with the T91A mutation (603945.0001).
In 2 patients with leukoencephalopathy with vanishing white matter (VWM5; 620315), Leegwater et al. (2001) found compound heterozygosity for a gly386-to-val (G386V) mutation and an arg113-to-his mutation (R113H; 603945.0004) in the EIF2B5 gene. The G386V amino acid substitution was the result of a c.1157G-T transversion that affected the first nucleotide in exon 8 and may have disturbed splicing. The R113H substitution results from a 338G-A transition in the EIF2B5 gene. Leegwater et al. (2001) identified the R113H mutation in 12 families with VWM, with a total allelic frequency of approximately 20% in the group of affected individuals that they investigated.
For discussion of the arg113-to-his (R113H) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Leegwater et al. (2001), see 603945.0003.
In a woman with adult onset of VWM diagnosed at the age of 27 years, Biancheri et al. (2003) identified homozygosity for the R113H mutation, which they originally incorrectly reported as R118H.
In 3 of 6 families with VWM and ovarian failure, which the authors designated 'ovarioleukodystrophy,' Fogli et al. (2003) identified the R113H mutation. Patients from these families had the mildest form of the disease. Fogli et al. (2003) stated that the R113H mutation had been found in 22% of chromosomes of 41 patients with VWM (Leegwater et al., 2001). Because R113 is not conserved among species, and because H is found at this position in rat and mouse, they suggested that the homozygous R113H mutation in humans may not strongly affect EIF2B5 function. One patient studied by Fogli et al. (2003), who had early secondary amenorrhea, was a compound heterozygote for the R113H mutation and an arg195-to-cys mutation (R195C; 603945.0007).
Van der Knaap et al. (2004) identified 6 individuals who were homozygous for the R113H mutation; 2 of them were sibs. Five of the 6 had an unusually mild form of VWM, 4 with a late-adolescent or adult onset, and 1 with childhood onset. One individual was asymptomatic at age 30 years.
Fogli et al. (2002) studied the EIF2B5 gene in 3 patients of 2 Cree families with Cree leukoencephalopathy (VWM5; 620315) and identified a homozygous G-to-A transition at nucleotide 584, resulting in an arg195-to-his (R195H) substitution. They reported an unpublished observation of the same R195H mutation in a CACH/VWM family from the Highlands in Scotland. The northern Quebec Cree first encountered Europeans in the early 1700s; these were Scottish fur traders from the Hudson Bay Trading Company. Fogli et al. (2002) stated that the probands from the 2 Cree families in their report could trace their paternal ancestry to 3 English Hudson Bay Company employees around 1770.
In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter (VWM5; 620315), Fogli et al. (2002) identified a homozygous 925G-C mutation in the EIF2B5 gene, resulting in a leu309-to-val (L309V) substitution. The unaffected parents were heterozygous for the mutation.
In a patient with VWM and ovarian failure (VWM5; 620315) with early-onset secondary amenorrhea, Fogli et al. (2003) found compound heterozygosity for the arg113-to-his mutation (R113H; 603945.0004) and an arg195-to-cys (R195C) mutation in the EIF2B5 gene. The R195C mutation resulted from a C-to-T transition at nucleotide 583. The authors noted that the R195C mutation involved the same codon as that mutated in Cree leukoencephalopathy, which is caused by homozygosity for arg195 to his (R195H; 603945.0005).
In a Japanese woman, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Ohtake et al. (2004) identified a homozygous 545C-T transition in exon 4 of the EIF2B5 gene, resulting in a thr182-to-met (T182M) substitution. The patient presented with presenile dementia and psychiatric symptoms.
In 4 patients from 2 unrelated families with early-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Passemard et al. (2007) identified compound heterozygosity for mutations in the EIF2B5 gene. In a brother and sister, they identified a 944G-A transition resulting in an arg315-to-his (R315H) substitution and a 166T-G transversion resulting in a phe56-to-val (F56V; 603945.0010) substitution. In 2 sisters, they identified the R315H mutation and a 167T-G transversion resulting in a phe56-to-cys (F56C; 603945.0011) substitution. In the first family, the 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 sister who survived beyond age 3 years developed macrocephaly. Passemard et al. (2007) suggested that altered brain water balance may result in swelling of the disease white matter and macrocephaly in some patients with VWM disease.
For discussion of the phe56-to-val (F56V) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Passemard et al. (2007), see 603945.0009.
For discussion of the phe56-to-cys (F56C) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Passemard et al. (2007), see 603945.0009.
In a 53-year-old Japanese man, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Matsukawa et al. (2011) identified a homozygous 808G-C transversion in the EIF2B5 gene, resulting in an asp270-to-his (D270H) substitution. The mutation was not found in 96 Japanese control individuals. The patient developed progressive gait unsteadiness and miscalculation at age 50. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
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