Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2S3
SNOMEDCT: 722037004;
Cytogenetic location: Xp22.11 Genomic coordinates (GRCh38): X:24,054,956-24,078,810 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.11 | MEHMO syndrome | 300148 | X-linked recessive | 3 |
The EIF2S3 gene encodes the core subunit of eukaryotic translation initiation factor-2 (eIF2), a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40S ribosomal subunit. The eIF2 complex is essential for protein synthesis (summary by Moortgat et al., 2016).
Gaspar et al. (1994) cloned a human cDNA encoding the largest subunit of eIF-2, EIF2G. The EIF2G cDNA encodes a 472-amino acid protein with a molecular mass of 51.8 kD and contains 3 consensus GTP-binding elements. Human EIF2G is highly related to the yeast homolog, GCD11, exhibiting 71% sequence identity and an additional 13% similarity.
By in situ hybridization in human embryos, Gregory et al. (2019) observed EIF2S3 mRNA transcripts in the hypothalamus and Rathke pouch, anterior and posterior pituitary, progenitor cells of the nasal epithelium, and the retina, at Carnegie stages 20 and 23. EIF2S3 transcripts were also strongly detected in the pancreas of a 13-week human fetus.
Ehrmann et al. (1998) mapped the EIF2S3 gene to chromosome Xp21 by isotopic in situ hybridization. The largest number of grains were located on the region Xp22.2-p22.1. A secondary hybridization repeat was detected on 12p13.2-p12.3. No significant accumulation of grains was detected on the Y chromosome.
Genes controlling the functions of spermatogenesis, Spy, and expression of the male-specific minor transplantation antigen H-Y, Hya (426000), map to a region of the short arm of the mouse Y chromosome, delta-Sxr(b), that lies between the zinc finger genes Zfy1 and Zfy2 (490000) and is deleted in Sxr(b) mutant mice. These Sxr(b) mice arose from an original sex-reversed mutation, Sxr(a), that carries a duplication of most of the Y chromosome short arm translocated to the telomeric end of the pseudoautosomal region of the Y chromosome. Several genes were mapped to that interval of the mouse Y chromosome and each was found to have a homolog on the X chromosome. Four of them, Zfy1 and Zfy2 (490000), Ube1y (489000), and Dffry (400005), are expressed specifically in the testis and their X homologs (Zfx, 314980; Ube1x, 314370; Dffrx, 300072) are not transcribed from the inactive X chromosome. A further 2, Smyc (426000) and Uty (400009), are ubiquitously expressed and their X homologs (Jarid1c/Smcx, 314690; Utx, 300128) escape X inactivation. Ehrmann et al. (1998) identified another gene from this region of the mouse Y chromosome. It was found to encode the highly conserved eukaryotic translation initiation factor eIF-2-gamma. In the mouse this gene was found to be ubiquitously expressed, to have an X chromosome homolog that maps close to Dmd (300377), and to escape X inactivation. The coding regions of the X and Y genes show 86% nucleotide identity and encode the putative products with 98% amino acid identity. Ehrmann et al. (1998) found that the human homolog is located on Xp21 and also escapes X inactivation. No evidence of a Y copy of this gene was found in humans, however. In both humans and mice, Ehrmann et al. (1998) identified autosomal retroposons of EIF2G in both humans and mice and an additional retroposon on the X chromosome in some mouse strains. Ark blot analysis of eutherian and metatherian genomic DNA indicated that X-Y homologs are present in all species tested except in simian primates and kangaroo and that retroposons are common to a wide range of mammals. ('Zoo blots' are Southern blots of genomic DNA from multiple species without regard to gender; 'ark blots' are Southern blots used to compare male and female from multiple species.)
Using an integrative lentiviral vector expressing EIF2S3-targeting shRNA, Gregory et al. (2019) generated human hybrid pancreatic cells with stable knockdown of EIF2S3. The transduced cells failed to survive for as long as control cell populations, and the EIF2S3-knockdown cell line had significantly higher basal and cytokine-stimulated caspase activities compared to control cells, suggesting increased apoptosis. The authors noted that the impaired cell survival and increased caspase activities in the EIF2S3-knockdown human cell line was consistent with an essential role for eIF2-gamma in initiating protein synthesis within the cell.
In 3 males from a consanguineous family of Moroccan Jewish ancestry with a syndromic X-linked mental retardation resembling MEHMO (300148), Borck et al. (2012) identified a hemizygous missense mutation in the EIF2S3 gene (I222T; 300161.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Female carriers were unaffected. In vitro functional expression assays in yeast and in human cells showed that the mutation impaired binding to EIF2B (see, e.g., EIF2B1, 606686) and disrupted EIF2 complex formation, resulting in defects in translation initiation.
In affected members of 2 unrelated families with MEHMO, Moortgat et al. (2016) identified 2 different hemizygous mutations in the EIF2S3 gene: a missense mutation (I259M; 300161.0002), resulting in a slightly less severe phenotype, and a frameshift mutation (300161.0003), resulting in a more severe phenotype with death in infancy. Functional studies of the variant and studies of patient cells were not performed.
In affected members of 4 families with MEHMO, including the original family reported by Steinmuller et al. (1998), Skopkova et al. (2017) identified mutations in the EIF2S3 gene: a frameshift mutation (Ile465Serfs; 300161.0004) in 3 families, and a missense mutation (S108R; 300161.0005) in 1 patient who had a milder form of the syndrome.
In monozygotic male twins and their maternal male cousin who had hypopituitarism with glucose dysregulation, Gregory et al. (2019) sequenced the X chromosome and identified hemizygosity for a missense mutation in the EIF2S3 gene (P432S; 300161.0006) that segregated as expected in the family and was not found in public variant databases. Screening for EIF2S3 variants in a cohort of 103 patients with various congenital hypopituitarism phenotypes, with or without midline structural brain defects on MRI, did not yield any further pathogenic variants. Yeast assays showed that the P432S variant impairs eIF2 function to a modest degree, less than the MEHMO-associated I259M variant (300161.0002) but to a degree comparable to that observed with the MEHMO-associated I222T (300161.0001) and Ile465SerfsTer4 (300161.0004) variants. In addition, the authors suggested that the P432S variant might cause disease by altering the fidelity of translation start-site selection.
Moortgat et al. (2016) found that morpholino knockdown of eif2s3 in zebrafish resulted in morphologic defects, including morphants being shorter with a curved tail, smaller head, and small eyes compared to wildtype. Morphants also showed hypomotility.
In 3 males from a consanguineous family of Moroccan Jewish ancestry with an X-linked mental retardation syndrome (MEHMO; 300148), Borck et al. (2012) identified a hemizygous c.665T-C transition (c.665T-C, NM_001415.3) in the EIF2S3 gene, resulting in an ile222-to-thr (I222T) substitution at a conserved residue in the animal kingdom. The residue is located in the GTP-binding domain. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Sequencing Project databases. Specific mutation of the corresponding residue (V281K) in the yeast homolog substantially impaired yeast growth, impaired binding to eif2-beta (see, e.g., EIF2B1, 606686), and resulted in defects in translation initiation with decreased fidelity of start site selection. Coimmunoprecipitation studies in HeLa cells showed that the I222T mutation disrupted EIF2 complex formation by impairing the binding of EIF2B to EIF2G.
In 2 maternal half brothers, born of unrelated Belgian parents, with an X-linked mental retardation syndrome (MEHMO; 300148), Moortgat et al. (2016) identified a hemizygous c.777T-G transversion (c.777T-G, NM_001415.3) in the EIF2S3 gene, resulting in an ile259-to-met (I259M) substitution at a conserved residue in a functional domain that binds the eIF2-alpha subunit and Met-tRNA. The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 135), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
In a male infant, born of unrelated parents of Spanish origin, with an X-linked mental retardation syndrome (MEHMO; 300148), Moortgat et al. (2016) identified a hemizygous 4-bp deletion (c.1394_1397del, NM_001415.3) in the EIF2S3 gene, resulting in a frameshift and premature termination (Ile465SerfsTer4). The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 135), 1000 Genomes Project, Exome Variant Server, or ExAC databases. There were 3 similarly affected deceased male family members, but their DNA was not available for study. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function in males. The patient had a severe phenotype: he never achieved head control or visual contact, and he died at age 12 months.
In affected males in 3 families (F1, F2, F3) with MEHMO syndrome (MEHMO; 300148), including the original family reported by Steinmuller et al. (1998), Skopkova et al. (2017) identified a 4-bp deletion (c.1394_1397delTCAA, NM_001415.3) in the last exon of the EIF2S3 gene, resulting in a frameshift and a premature termination codon (Ile465SerfsTer4). The mutations, which were found by whole-exome or X-chromosome exome sequencing, were confirmed by Sanger sequencing. The mutation segregated with the phenotype in all 3 families and was not present in the dbSNP (build 147) or ExAC databases. Studies in yeast showed that the orthologous mutation impaired translation initiation and decreased fidelity of start codon selection. Studies in patient fibroblasts confirmed an increased integrated stress response due to the mutation.
In a patient (F4) with MEHMO syndrome (MEHMO; 300148), Skopkova et al. (2017) identified a c.324T-A transversion (c.324T-A, NM_001415.3) in the EIF2S3 gene, resulting in a ser108-to-arg (S108R) substitution at a highly conserved residue. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient inherited the mutation from his unaffected mother but his healthy brother was unavailable for testing. The mutation was not present in the dbSNP (build 147) or ExAC databases.
In monozygotic male twins and their maternal male cousin who had mild learning difficulties, hypopituitarism with GH and TSH deficiencies, and glucose dysregulation (MEHMO; 300148), Gregory et al. (2019) identified hemizygosity for a c.1294C-T transition (c.1294C-T, NM_001415) in the EIF2S3 gene, resulting in a pro432-to-ser (P432S) substitution at a highly conserved residue in the C-terminal domain. The mutation was inherited from their heterozygous mothers, who were sisters, and was also present in the maternal grandmother; it was not found in the ExAC or gnomAD databases. Yeast assays showed that the mutant protein impaired eIF2 function to modest degree compared to wildtype EIF2S3. In addition, the P432S variant showed an approximately 2-fold increase in non-AUG initiation compared to wildtype EIF2S3, suggesting relaxed start-site selection stringency. The patients did not have microcephaly, epilepsy, or obesity; Gregory et al. (2019) suggested that untreated hypoketotic hypoglycemia in previously reported patients with MEHMO may have contributed to their more severe phenotype.
Borck, G., Shin, B.-S., Stiller, B., Mimouni-Bloch, A., Thiele, H., Kim, J.-R., Thakur, M., Skinner, C., Aschenbach, L., Smirin-Yosef, P., Har-Zahav, A., Nurnberg, G., and 12 others. eIF2-gamma mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Molec. Cell 48: 641-646, 2012. [PubMed: 23063529] [Full Text: https://doi.org/10.1016/j.molcel.2012.09.005]
Ehrmann, I. E., Ellis, P. S., Mazeyrat, S., Duthie, S., Brockdorff, N., Mattei, M. G., Gavin, M. A., Affara, N. A., Brown, G. M., Simpson, E., Mitchell, M. J., Scott, D. M. Characterization of genes encoding translation initiation factor eIF-2-gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution. Hum. Molec. Genet. 7: 1725-1737, 1998. [PubMed: 9736774] [Full Text: https://doi.org/10.1093/hmg/7.11.1725]
Gaspar, N. J., Kinzy, T. G., Scherer, B. J., Humbelin, M., Hershey, J. W. B., Merrick, W. C. Translation initiation factor eIF-2: cloning and expression of the human cDNA encoding the gamma-subunit. J. Biol. Chem. 269: 3415-3422, 1994. [PubMed: 8106381]
Gregory, L. C., Ferreira, C. B., Young-Baird, S. K., Williams, H. J., Harakalova, M., van Haaften, G., Rahman, S. A., Gaston-Massuet, C., Kelberman, D., GOSgene, Qasim, W., Camper, S. A., Dever, T. E., Shah, P., Robinson, I. C. A. F., Dattani, M. T. Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. EBioMedicine 42: 470-480, 2019. [PubMed: 30878599] [Full Text: https://doi.org/10.1016/j.ebiom.2019.03.013]
Moortgat, S., Desir, J., Benoit, V., Boulanger, S., Pendeville, H., Nassogne, M.-C., Lederer, D., Maystadt, I. Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. Am. J. Med. Genet. 170A: 2927-2933, 2016. [PubMed: 27333055] [Full Text: https://doi.org/10.1002/ajmg.a.37792]
Skopkova, M., Hennig, F., Shin, B.-S., Turner, C. E., Stanikova, D., Brennerova, K., Stanik, J., Fischer, U., Henden, L., Muller, U., Steinberger, D., Leshinsky-Silver, E., and 14 others. EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum. Mutat. 38: 409-425, 2017. [PubMed: 28055140] [Full Text: https://doi.org/10.1002/humu.23170]
Steinmuller, R., Steinberger, D., Muller, U. MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1-p22.13. Europ. J. Hum. Genet. 6: 201-206, 1998. [PubMed: 9781023] [Full Text: https://doi.org/10.1038/sj.ejhg.5200180]