EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome
Abstract
Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.
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In mice, homozygous deletion of the gene encoding PERK causes massive and rapid β-cell apoptosis, leading to infantile diabetes.
“Coherently, in mice homozygous deletion of the gene encoding PERK causes massive and rapid β-cell apoptosis, leading to infantile diabetes.”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [393]
β-cells in Perk-null mice are distended with electron-dense proteinaceous material and exhibit a high rate of apoptosis.
“Interestingly, β-cells in Perk-null mice are distended with electron-dense proteinaceous material, also exhibiting a high rate of apoptosis [393,394].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [393]
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“Interestingly, β-cells in Perk-null mice are distended with electron-dense proteinaceous material, also exhibiting a high rate of apoptosis [393,394].”
Background
- Authors
- Delépine, M., Nicolino, M., Barrett, T., Golamaully, M., Mark Lathrop, G., & Julier, C.
- Affiliations
- Hôpital Debrousse (FR)
- Birmingham Children's Hospital (GB)
- Centre for Human Genetics (GB)
- Corresponding author
- Julier, Cécile
- Venue
- Nature Genetics
- Published
- 2000-08
- Volume
- 25
- Issue
- 4
- Pages
- 406-409
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1505761263
- Cited by
- 813
- References
- 30
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 23 · 2023: 24 · 2022: 28 · 2021: 39 · 2020: 33 · 2019: 29 · 2018: 35 · 2017: 32 · 2016: 23 · 2015: 28 · 2014: 49 · 2013: 37 · 2012: 48
- FWCI
- 15.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- PERK, Wolcott-Rallison syndrome, diabetes mellitus, epiphyseal dysplasia, osteoporosis, growth retardation, consanguineous family, linkage mapping, catalytic domain mutations, autosomal recessive disorder, candidate gene identification
- MeSH terms
- Abnormalities, Multiple, Amino Acid Sequence, Base Sequence, Diabetes Mellitus, Type 1, DNA, DNA Mutational Analysis, Epiphyses, Family Health, Female, Gene Frequency, Genotype, Growth Disorders, Haplotypes, Humans, Infant, Male, Molecular Sequence Data, Mutation, Pedigree, Polymorphism, Genetic, Syndrome, Sequence Homology, Amino Acid, Microsatellite Repeats, eIF-2 Kinase
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