Alternative titles; symbols
HGNC Approved Gene Symbol: EIF4G1
Cytogenetic location: 3q27.1 Genomic coordinates (GRCh38): 3:184,314,606-184,335,358 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q27.1 | {Parkinson disease 18} | 614251 | Autosomal dominant | 3 |
All eukaryotic cellular messenger RNAs are posttranscriptionally modified by addition of an m(7)GTP moiety to the 5-prime terminus, referred to as a cap. Recognition of the cap structure and unwinding of mRNA secondary structure during the initiation phase of protein synthesis is catalyzed by initiation factors of the eIF4 group. eIF4E (133440) is a 25-kD cap-binding protein. eIF4A (see 602641) is a 46-kD polypeptide that possesses ATP-dependent RNA helicase activity and RNA-dependent ATPase activity. eIF4B (603928) is a 69-kD RNA-binding protein that enhances the activity of eIF4A. eIF4-gamma, also known as p220, is a 154-kD protein that forms various complexes with the other eIF4 polypeptides. The complex of eIF4A, eIF4E, and eIF4-gamma has been referred to as either eIF4F or eIF4. Collectively, these factors facilitate the recruitment of mRNA to the ribosome, which is the rate-limiting step for protein synthesis under normal conditions. eIF4-gamma is the target for proteolytic cleavage during picornavirus infection, an event that is thought to be responsible for the inhibition of host cellular mRNA translation (Yan and Rhoads, 1995).
By screening a rabbit brain library with oligonucleotide probes based on the sequence of rabbit eIF4-gamma peptides, Yan et al. (1992) identified partial eIF4-gamma cDNAs. They used the rabbit cDNAs as probes and isolated human brain cDNAs encoding eIF4-gamma. The predicted human protein contains 1,396 amino acids. Western blot analysis of poliovirus-infected HeLa cell extracts revealed that eIF4-gamma has an apparent molecular mass of 200 to 220 kD and is cleaved by this picornavirus.
Imataka and Sonenberg (1997) stated that the N-terminal region of eIF4G contains a binding site for eIF4E. They demonstrated that the central third of eIF4G contains an eIF3 (see 602039)-binding region and an eIF4A-binding domain. A second, separate eIF4A-binding site is present in the C-terminal third. Neither eIF4A-binding domain alone activates translation. In contrast to eIF4G, the eIF4G-related translation regulator p97 (602325) binds eIF4A only through its N-terminal domain, which is homologous to the central domain of eIF4G.
Gradi et al. (1998) identified a second human eIF4G gene. They designated the original gene eIF4GI and the novel gene eIF4GII (EIF4G3; 603929).
Imataka et al. (1998) found that the human eIF4GI protein contains an additional 156 N-terminal amino acids compared to the sequence published by Yan et al. (1992). They demonstrated that this N-terminal region binds poly(A)-binding protein (PABP; 604679).
Imataka et al. (1998) found that, in an in vitro translation system, an N-terminal fragment of eIF4GI that included the PABP-binding site inhibited poly(A)-dependent translation, but had no effect on translation of a deadenylated mRNA. Imataka et al. (1998) concluded that eIF4G probably functions in poly(A)-dependent translation in mammalian cells.
Using coimmunoprecipitation experiments, Pyronnet et al. (1999) demonstrated that MNK1 (MKNK1; 606724) is associated with the eIF4F complex via an interaction with the C-terminal region of eIF4G. They hypothesized that eIF4G provides a docking site for Mnk1 to phosphorylate eIF4E.
Cytokine and protooncogene mRNAs are rapidly degraded through AU-rich elements in the 3-prime untranslated region. Rapid decay involves AU-rich binding protein AUF1 (601324), which complexes with heat-shock proteins HSC70 (600816) and HSP70 (see 140550), translation initiation factor EIF4G, and PABP. AU-rich mRNA decay is associated with displacement of EIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of HSP70 by heat shock, downregulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 (314370), all result in HSP70 sequestration of AUF1 in the perinucleus-nucleus, and all 3 processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway (Laroia et al., 1999).
Amplification of cellular oncogenes is an important mechanism of altered gene expression in human cancers. Using comparative genomic hybridization, Brass et al. (1997) identified amplification at 3q26.1-q26.3 in 30% of squamous cell carcinomas of the lung. They then combined an immunologic and molecular genetic approach to identify amplified and tumor-relevant genes. They generated a cDNA expression library from a tumor with the 3q amplification and hybridized the expressed recombinant polypeptides with the autologous serum. In this way they identified 17 antigens that induced an immune response in a patient with squamous cell carcinoma. Four of the 17 cDNAs were nearly identical with the eukaryotic translation initiation factor EIF4G. They demonstrated that the EIF4G gene was amplified within 3q26-q27 in independent squamous cell lung carcinomas.
E-cadherin (CDH1; 192090), an epithelial marker, is anchored at the epithelial cell surface through interaction with p120 catenin (CTNND1; 601045). In inflammatory breast cancer, elevated cell surface expression of E-cadherin causes tumor cells to cluster together in nonadherent emboli rather than to adhere to stroma. Silvera et al. (2009) found that EIF4G1 was overexpressed in a significant number of inflammatory breast cancers. Silencing of EIF4G1 in SUM149 breast cancer cells via short hairpin RNA reduced EIF4G1-dependent translation of p120 mRNA, resulting in reduced cell surface E-cadherin expression and reduced tumorigenic potential of SUM149 cells.
Thoreen et al. (2012) used high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR (601231) inhibitor Torin-1, which, unlike rapamycin, fully inhibits mTOR complex 1 (mTORC1). Their data revealed a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5-prime terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 (140572) and Ybx1 (154030), with previously unrecognized TOP or related TOP-like motifs that were identified. Thoreen et al. (2012) found no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5-prime untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4EBP family of translational repressors (see 602223), arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin-1. The E4BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E (133440) and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation.
Boussemart et al. (2014) demonstrated that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein, and the eIF4A (602641) RNA helicase, is associated with resistance to anti-BRAF (164757), anti-MEK (176872), and anti-BRAF plus anti-MEK drug combinations in BRAF(V600) (164757.0001)-mutant melanoma, colon, and thyroid cancer cell lines. Resistance to treatment and maintenance of eIF4F complex formation is associated with 1 of 3 mechanisms: reactivation of MAPK (see 176948) signaling; persistent ERK-independent phosphorylation of the inhibitory eIF4E-binding protein 4EBP1 (602223); or increased proapoptotic BMF (606266)-dependent degradation of eIF4G. The development of an in situ method to detect the eIF4E-eIF4G interactions showed that eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases compared to tumors before treatment. Strikingly, inhibiting the eIF4F complex, either by blocking the eIF4E-eIF4G interaction or by targeting eIF4A, synergized with inhibiting BRAF(V600) to kill the cancer cells. eIF4F appeared not only to be an indicator of both innate and acquired resistance, but also a therapeutic target. Boussemart et al. (2014) concluded that combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms in BRAF(V600)-mutant cancers.
Using a single-molecule assay, Garcia-Garcia et al. (2015) found that eiF4A functions as an adenosine triphosphate-dependent processive helicase when complexed with 2 accessory proteins, eIF4G and eIf4B (603928). Translocation occurred in discrete steps of 11 +/- 2 basepairs, irrespective of the accessory factor combination. Garcia-Garcia et al. (2015) concluded that their findings supported a memoryless stepwise mechanism for translation initiation and suggested that similar factor-dependent processivity may be shared by other members of the DEAD-box helicase family.
Scaffold protein eIF4G1 in the eIF4F complex binds to the m7G-cap-binding protein eIF4E and the RNA helicase eIF4A. EIF4G1 can also directly interact with eIF1 (619901), and both eIF1 and eIF4G1 are required for scanning and AUG selection in mammalian translation. Using immunoprecipitation analysis, Haimov et al. (2018) showed that interaction of eIF4E and eIF1 with eIF4G1 was mutually exclusive, as eIF4G1 coprecipitated either with eIF4E or eIF1, but not both. Mutation analysis showed that the eIF1 surface residues K109 and H111 were important for interaction with eIF4G1. Knockdown analysis in HEK293T cells revealed that eIF1-eIF4G1 interaction was required for leaky scanning, in particular for avoiding m7G-cap-proximal AUG. EIF4E-eIF4G1 antagonized scanning promoted by eIF1-eIF4G1, and eIF4G1 needed to dissociate itself from eIF4E and engage with eIF1 to promote scanning activity. Mapping the binding sites on eIF4G1 identified a binding site for eIF1. However, in addition to the major eIF4E-binding site on eIF4G1, eIF4E also indirectly bound to the eIF1-binding site, and eIF1 and eIF4E competed for the shared binding site on eIF4G1.
Gross et al. (2003) reported the solution structure of the complex between yeast Eif4e and the Eif4e-binding region of Eif4g (amino acids 393 to 490). Binding between these proteins triggered folding of the N terminus of Eif4e with concomitant folding of Eif4g through a mutually induced fit mechanism. Protein binding altered the conformation and/or the stability of the cap binding slot, resulting in enhanced association of Eif4e with the cap structure. Dissociation of the ternary complex was slow, and the N terminus of Eif4e was required for these effects. Yeast strains harboring mutants of Eif4e lacking key N-terminal residues showed impaired growth, decreased polysome content, and reduced interaction between Eif4e and Eif4g.
Using PCR analysis of human genomic DNA from human/hamster somatic cell hybrids, Yan and Rhoads (1995) mapped the EIF4G gene to chromosome 3q27-qter. Brass et al. (1997) confirmed the localization of EIF4G to 3q27 by fluorescence in situ hybridization.
In affected members of a large French family with late-onset Parkinson disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011) identified a heterozygous mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of genomewide linkage analysis followed by direct sequencing. The EIF4G1 gene was subsequently sequenced in 95 probands with autosomal dominant parkinsonism and 130 pathologically-defined cases of Lewy body disease, which revealed 4 additional different missense mutations in 2 PD patients and 2 Lewy body disease cases. These 4 variants were then genotyped in a case-control series consisting of 4,483 individuals with idiopathic PD and 3,865 controls: 3 additional patients carried only 2 of the variants, 2 with A502V (600495.0002) and 1 with a G686C substitution. Coimmunoprecipitation studies indicated that the R1205H and A502V substitutions impaired formation of the larger translation initiation complex. The results were compatible with a dominant-negative loss of function and age-dependent neurodegeneration. Hydroperoxide treatment caused a profound loss of mitochondrial membrane potential in cells expressing the mutations compared to cells with wildtype protein. The findings implicated defects in mRNA translation initiation in Parkinson disease. Chartier-Harlin et al. (2011) postulated that the mutations hindered the ability of cells to respond rapidly and dynamically to stress, presumably through changes in the translation of existing mRNAs essential to cell survival.
By whole-exome sequencing targeting the EIF4G1 gene in 213 patients with Parkinson disease, Nuytemans et al. (2013) identified 1 proband who carried a heterozygous R1205H variant (rs112176450) that segregated with the disorder in the family. However, the variant was also found in an asymptomatic 86-year-old family member, indicating incomplete penetrance. Several additional rare variants were identified in the EIF4G1 gene, but association studies excluded an overall major contribution of genetic variability in this gene to development of the disorder. Functional studies were not performed.
Huttenlocher et al. (2015) assessed the relevance of EIF4G1 mutations in a European cohort of 2,146 patients with Parkinson disease. Of these, 2,051 sporadic PD patients were screened for the reported A502V and R1205H mutations. In addition, the complete coding region of EIF4G1 was directly sequenced in 95 familial PD patients with autosomal dominant inheritance. Huttenlocher et al. (2015) also imputed the R1205H substitution and tested for association with PD in the Icelandic population (93,698 samples). The authors did not observe the A502V substitution in their cohort; however, the R1205H mutation was identified in 1 sporadic PD patient. Using haplotype imputing, Huttenlocher et al. (2015) found the same mutation in 76 Icelandic subjects older than 65 years; only 5 of these subjects reported PD symptoms (OR 1.3, p = 0.50). The authors concluded that, if causal, the R1205H mutation in the EIF4G1 gene has a low penetrance or a late-onset manifestation.
Huttenlocher et al. (2015) identified 3 nonsynonymous or silent variations in EIF4G1. The arg566-to-cys (R566C) variant did not segregate within a family with Parkinson disease. Huttenlocher et al. (2015) considered all further recently published EIF4G1 mutations found in their cohort to be benign polymorphisms.
In 10 affected members of a large French family with late-onset Parkinson disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011) identified a heterozygous 3614G-A transition in exon 24 of the EIF4G1 gene, resulting in an arg1205-to-his (R1205H) substitution in a highly conserved region. Among a cohort of 4,708 PD patients screened for R1205H, 9 patients from 7 families from the US, Canada, Ireland, Italy, and Tunisia were found to carry the mutation. Haplotype analysis indicated a founder effect in these families and in the French family. The mutation was not found in at least 4,050 controls. Coimmunoprecipitation studies indicated that the R1205H substitution perturbs EIF4G1 binding to EIF3E (602210), which impairs formation of the larger translation initiation complex. The results were compatible with a dominant-negative loss of function and age-dependent neurodegeneration. Hydroperoxide treatment caused a profound loss of mitochondrial membrane potential in cells expressing the mutation compared to cells with wildtype protein.
Nuytemans et al. (2013) identified a heterozygous R1205H variant (rs112176450) in 3 members of a family who had onset of Parkinson disease at ages 54, 57, and 73 years, respectively. Two additional family members who carried the variant, a 90-year-old man with postural instability who was wheelchair-bound but had an unclear diagnosis, and an asymptomatic 86-year-old woman, indicated incomplete penetrance. The variant was not observed in 85 control individuals and was present at low frequency (0.02%) in the Exome Variant Server database. The proband was ascertained from 213 patients with PD who underwent whole-exome sequencing targeting the EIF4G1 gene.
Huttenlocher et al. (2015) identified the R1205H mutation in 1 individual from a cohort of 2,146 European PD patients who were assessed to determine the relevance of EIF4G1 mutations. Using haplotype imputing, the authors also found this mutation in 76 Icelandic subjects older than 65 years; only 5 of these subjects reported PD symptoms (OR 1.3, p = 0.50). Huttenlocher et al. (2015) concluded that, if causal, the R1205H mutation in the EIF4G1 gene has a low penetrance or a late-onset manifestation.
In affected members of 4 unrelated families with Parkinson disease-18 (PARK18; 614251), Chartier-Harlin et al. (2011) identified a heterozygous 1505C-T transition in exon 10 of the EIF4G1 gene, resulting in an ala502-to-val (A502V) substitution. The mutation was not found in over 3,865 controls and was conserved in most mammals, but was found in the rabbit. Haplotype analysis suggested a founder effect. Coimmunoprecipitation studies indicated that the A502V substitution perturbs EIF4G1 binding to EIF4E (133440), which impairs formation of the larger translation initiation complex. The results were compatible with a dominant-negative loss of function and age-dependent neurodegeneration. Hydroperoxide treatment caused a profound loss of mitochondrial membrane potential in cells expressing the mutation compared to cells with wildtype protein.
Huttenlocher et al. (2015) did not find the A502V mutation in a cohort of 2,146 European PD patients who were assessed to determine the relevance of EIF4G1 mutations.
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