Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2AK3
SNOMEDCT: 254066006;
Cytogenetic location: 2p11.2 Genomic coordinates (GRCh38): 2:88,556,741-88,628,145 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p11.2 | Wolcott-Rallison syndrome | 226980 | Autosomal recessive | 3 |
In response to various environmental stresses, eukaryotic cells downregulate protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor-2 (eIF2-alpha; 603907). Phosphorylation of eIF2-alpha results in inhibition of the guanine nucleotide exchange factor eIF-2B (see EIF2B5; 603945), thereby reducing the rate of the GDP to GTP exchange that is required for eIF2 to carry out additional rounds of translation initiation. The eukaryotic eIF2-alpha kinases PKR (176871), HRI (EIF2AK1; 613635) , and yeast GCN2 share extensive homology within their catalytic domains, but have distinct regulatory domains allowing for different physiologic signals to regulate phosphorylation of eIF2-alpha. Shi et al. (1998) identified a rat eIF2-alpha kinase that they designated PEK (pancreatic eIF2-alpha kinase). The authors demonstrated that PEK regulated protein synthesis both in vitro and in vivo.
By searching an EST database for sequences related to rat PEK, Shi et al. (1999) identified partial cDNAs encoding human PEK. Using a combination of techniques, they cloned additional cDNAs and genomic fragments corresponding to the entire human PEK coding region. The predicted 1,115-amino acid human protein is 88% identical to rat PEK. PEK contains an N-terminal signal peptide and a hydrophobic region. The kinase domain of human PEK is similar to that of the other eIF2-alpha kinases, but the 550-residue N-terminal region is unique, perhaps reflecting the different physiologic signals that regulate its activity. Like rat PEK, recombinant human PEK was autophosphorylated and specifically phosphorylated eIF2-alpha. Northern blot analysis revealed that the 5.2-kb PEK mRNA was expressed in all human tissues tested, with the highest expression in pancreas and placenta. However, using immunohistochemistry and immunofluorescence, Shi et al. (1999) detected PEK protein only in pancreatic delta cells. They concluded that PEK may play a role in regulating protein synthesis in the pancreatic islet, especially in delta cells.
By fluorescence in situ hybridization and radiation hybrid analysis, Hayes et al. (1999) mapped the EIF2AK3 gene to chromosome 2p12. Gross (2016) mapped the EIF2AK3 gene to chromosome 2p11.2 based on an alignment of the EIF2AK3 sequence (GenBank AF110146) with the genomic sequence (GRCh38).
Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation initiation. This response is likely mediated by increased phosphorylation of eIF2-alpha and is thought to reduce the workload imposed on the folding machinery during stress. Harding et al. (2000) reported that a targeted mutation of the mouse Eif2ak3 gene, which they called Perk, abolished the phosphorylation of eIF2-alpha in response to accumulation of malfolded proteins in the ER, resulting in abnormally elevated protein synthesis and higher levels of ER stress. Mutant cells were markedly impaired in their ability to survive ER stress, and inhibition of protein synthesis by cycloheximide treatment during ER stress ameliorated this impairment. The authors therefore concluded that PERK plays a major role in the ability of cells to adapt to ER stress.
Blais et al. (2004) determined that EIF2-alpha, PERK, ATF4 (604064), and GADD34 (PPP1R15A; 611048) are involved in an integrated adaptive response to hypoxic stress in HeLa cells.
Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was EIF2AK3. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown.
The 3 unfolded protein response (UPR) branches, governed by the ER stress sensors IRE1 (604033), PERK, and ATF6 (605537), promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. Lin et al. (2007) found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibitions and induction of the proapoptotic transcription regulator CHOP (126337), was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from their studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin (180380) in animal models of retinitis pigmentosa.
On the basis of 2 consanguineous families with Wolcott-Rallison syndrome (226980), Delepine et al. (2000) mapped the syndrome to a region of less than 3 cM on chromosome 2p12. Because the EIF2AK3 gene resides in this interval and is highly expressed in pancreatic islet cells, they explored it as a candidate and identified distinct homozygous mutations (604032.0001 and 604032.0002) segregating with the disorder in each of the 2 families.
In 2 unrelated patients with Wolcott-Rallison syndrome, Brickwood et al. (2003) identified 2 mutations in the EIF2AK3 gene (604032.0003-604032.0004). Additional phenotypic features included a predilection to severe unexplained hypoglycemic episodes suggestive of hepatic impairment, and to renal failure. It was noted that these features are not seen in Eif2ak3 knockout mice. Immunohistochemical analysis of human adult and fetal tissues showed that EIF2AK3 is widely expressed in the epithelial cells of the early fetal pancreas, and is present in adult beta cells and exocrine tissue. It is also expressed in developing bone, kidney, and adult liver, consistent with the extended phenotype of Wolcott-Rallison syndrome.
In 2 unrelated children with Wolcott-Rallison syndrome, Durocher et al. (2006) identified homozygosity for a nonsense mutation in the EIF2AK3 gene (604032.0005). The children exhibited disparate phenotypes; the authors suggested that there may be alternative pathways that can take over or supplement a defective metabolic pathway.
PERK couples protein folding in the ER to polypeptide biosynthesis by phosphorylating eIF2-alpha, attenuating translation initiation in response to ER stress. Perk is highly expressed in mouse pancreas, an organ active in protein secretion. Harding et al. (2001) presented a phenotypic characterization of Perk -/- mice. They found that under physiologic conditions, Perk was partially activated, accounting for much of the phosphorylated eIF2-alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk -/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1-alpha (604033) accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggested a special role for translational control in protecting secretory cells from ER stress.
Zhang et al. (2002) found that pancreata of Perk -/- mice were morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerated, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas showed reduced synthesis of several major digestive enzymes and succumbed to massive apoptosis after the fourth postnatal week. Perk -/- mice also exhibited skeletal dysplasia at birth and postnatal growth retardation. Skeletal defects included deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects were associated with defects in the rough ER of the major secretory cells of the skeletal system and pancreas.
In 3 affected Tunisian sibs with Wolcott-Rallison syndrome, Delepine et al. (2000) identified homozygosity for an insertion (T) at nucleotide position 1103 (1103insT) in the EIF2AK3 gene, creating a frameshift at amino acid position 345 and a premature termination at lys345. The mutation was not found in their unaffected parents, who were related as first cousins, or in their unaffected sib. The family had previously been reported by Nicolino et al. (1998).
In 2 children, born to consanguineous Pakistani parents, with Wolcott-Rallison syndrome (226980), Delepine et al. (2000) found homozygosity for a 1832G-A transition in the EIF2AK3 gene, resulting in a change of glutamine for arginine at position 587 (R587Q) within the catalytic domain.
Al-Gazali et al. (1995) reported the clinical findings in a patient with Wolcott-Rallison syndrome (226980), including spondyloepiphyseal dysplasia and generalized osteoporosis, up to the age of 4.5 years. Brickwood et al. (2003) identified a homozygous splice site mutation in the EIF2AK3 gene, IVS14+1G-A, in this patient. The mutation was predicted to result in a truncated protein that lacked the critical kinase domain. An offspring of consanguineous Saudi parents, the child was diagnosed at 2 months of age with diabetes requiring insulin therapy. The clinical course was marked by severe intellectual impairment and frequent unpredictable hypoglycemic episodes. A brother was also affected.
In a patient with Wolcott-Rallison syndrome (226980), the offspring of consanguineous Saudi parents, Brickwood et al. (2003) identified homozygosity for a 4-bp deletion (1563delGAAA) in the EIF2AK3 gene. The mutation caused a frameshift in exon 9 and a premature stop codon at amino acid 523. Both parents were heterozygous for the mutation. Management of this patient was complicated by recurrent hypoglycemia until death at age 2 years from severe diabetic ketoacidosis and infection. Skeletal features were consistent with spondyloepiphyseal dysplasia and included bilateral femoral fractures.
In 2 apparently unrelated children with Wolcott-Rallison syndrome (226980), born into 2 families from the same region of Quebec and sharing the same French surname, Durocher et al. (2006) identified homozygosity for a 994G-T transversion in exon 5 of the EIF2AK3 gene, resulting in a glu331-to-ter (E331X) substitution predicted to lead to a truncated protein of 330 amino acids, missing the cytosol-oriented kinase domain. The 2 children had disparate phenotypes: although both developed diabetes in infancy and had bone demineralization by x-ray, 1 died at age 4 of multiorgan failure after repeated episodes of hepatitis, whereas the other exhibited no hepatic or renal problems at 8 years of age.
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Gross, M. B. Personal Communication. Baltimore, Md. 2/17/2016.
Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., Ron, D. Diabetes mellitus and exocrine pancreatic dysfunction in Perk -/- mice reveals a role for translational control in secretory cell survival. Molec. Cell 7: 1153-1163, 2001. [PubMed: 11430819] [Full Text: https://doi.org/10.1016/s1097-2765(01)00264-7]
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Nicolino, P. M., Dupin, H., Macebeo, V., Treppoz, S., Chatelain, P. G. Wolcott-Rallison syndrome (diabetes mellitus and spondyloepiphyseal dysplasia) : a plausible existence of a gene(s) important for the mutation of neonatal pancreatic beta cell function. (Abstract) Hormone Res. 50 (suppl. 3): 77 only, 1998.
Shi, Y., An, J., Liang, J., Hayes, S. E., Sandusky, G. E., Stramm, L. E., Yang, N. N. Characterization of a mutant pancreatic eIF-2-alpha kinase, PEK, and co-localization with somatostatin in islet delta cells. J. Biol. Chem. 274: 5723-5730, 1999. [PubMed: 10026192] [Full Text: https://doi.org/10.1074/jbc.274.9.5723]
Shi, Y., Vattem, K. M., Sood, R., An, J., Liang, J., Stramm, L., Wek, R. C. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molec. Cell. Biol. 18: 7499-7509, 1998. [PubMed: 9819435] [Full Text: https://doi.org/10.1128/MCB.18.12.7499]
Zhang, P., McGrath, B., Li, S., Frank, A., Zambito, F., Reinert, J., Gannon, M., Ma, K., McNaughton, K., Cavener, D. R. The PERK eukaryotic initiation factor 2-alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Molec. Cell. Biol. 22: 3864-3874, 2002. [PubMed: 11997520] [Full Text: https://doi.org/10.1128/MCB.22.11.3864-3874.2002]