In adult pancreas, EIF2AK3 is expressed extensively in the islet, with a predominance in B cells. The normal birth weights of infants with Wolcott-Rallison syndrome and the unremarkable pancreatic organogenesis in Eif2ak3 -/- mice might suggest a minimal role for EIF2AK3 during pancreatic development in utero. Also, EIF2AK3 is widely expressed within the human fetal pancreas at eight weeks postconception, at which stage the organ is composed of epithelial progenitor cells before islet or exocrine differentiation. Taken together, these observations indicate that the human fetal pancreas may not be normal in Wolcott-Rallison syndrome. Consistent with this suggestion, mutation of the Eif2ak3 enzyme target (Ser51Ala of Eif2a) results in a 50% diminution of pancreatic insulin content between mouse embryonic days 16.5 and 18.5.
Mutations in the gene encoding the eukaryotic translation initiation factor 2-a kinase 3 (EIF2AK3, also called PERK or PEK) result in multiple epiphyseal dysplasia with early-onset diabetes mellitus. The EIF2AK3 enzyme phosphorylates EIF2A at Ser51 to regulate the synthesis of unfolded proteins in the endoplasmic reticulum. Targeted disruption of the Eif2ak3 gene in mice also causes diabetes because of the accumulation of unfolded proteins triggering B-cell apoptosis. Although these murine models have provided significant insight into the pathogenesis of Wolcott-Rallison syndrome, only few human cases have been characterized genetically.
Marafie et al. (2004) described a male patient with Wolcott-Rallison syndrome born to healthy parents who were first cousins. Chromosomal analysis revealed no abnormalities involving chromosomes 2p or 15q. No uniparental disomy of chromosome 6q was detected. However, a DNA sample was kept, with permission, for future mutation screening of the candidate gene. Marafie et al. (2004) expected that because of an increasing number of reports of Wolcott-Rallison syndrome in Arab children from the Arabian Peninsula there could be a quite large number of potential gene carriers in members of some highly inbred families from tribal origin in countries of the Gulf area.
Abdelrahman et al. (2000) reported a 3.5-year-old Saudi boy with Wolcott-Rallison syndrome. Bin-Abbas et al. (2001) extensively revised the case of Abdelrahman et al. (2000). One year later, Bin-Abbas et al. (2002) reported two sibs with an infantile onset of hyperglycemia, recurrent hepatitis, renal insufficiency, developmental delay, and skeletal epiphyseal dysplasia are described. In 2004, Senee et al. conducted genetic analysis on the boy reported by Abdelrahman et al. (2000) and Bin-Abbas et al. (2001). They also analyzed his brother who was much recently diagnosed with the disease. In both patients, Senee et al. (2004) found a nonsense (G-A) mutation at position 560 in the EIF2AK3 gene leading to a W163stop at the protein level. Senee et al. (2004) also conducted genetic analysis on the patients described by Bin-Abbas et al. (2002). At the time of analysis, a third sib was born to the family and was diagnosed with diabetes at 2 weeks of age. In both patients, Senee et al. (2004) found a deletion of 184 bp in exon15/intron15 of the EIF2AK3 gene. Such a deletion caused a frameshift starting at position 1024 of the gene with a stop signal at position 1047.
Nicolino et al. (1998) described a consanguineous family from Tunisia with Wolcott-Rallison syndrome. The family included three affected and one unaffected sibs with unaffected parents who were related as first cousins. In 2000, Delepine and colleagues conducted linkage analysis on the family members described by Nicolino et al. (1998). They mapped Wolcott-Rallison syndrome to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at four microsatellite markers within an interval of approximately 1 cM. Delepine et al. (2000) explored the gene encoding the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) since it resides in this interval. For this, they re-analyzed the family of Nicolino et al. (1998). They found 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. This mutation produces a truncated protein in which the entire catalytic domain is missing, probably resulting in complete loss of function. The mutation segregated with the disorder in the family. In 2004, Senee et al. conducted genetic analysis on the three affected sibs described by Nicolino et al. (1998) and confirmed the fact that all patients were homozygous for the insertion (T) at nucleotide position 1103 (1103insT) in the EIF2AK3 gene leading to premature termination at lys345.
Deeb et al. (2016) identified 25 cases of Neonatal Diabetes Mellitus (NDM) in Abu Dhabi between the years 1985-2013. Of these, 23 patients had Permanent Neonatal Diabetes Mellitus (PNDM). Genetic analysis revealed EIF2AK3 mutations causing Wolcott-Rallison Syndrome (WRS) in 9 of the PNDM patients. An additional patient with an EIF2AK3 mutation was diagnosed at 14 months and hence was not included in the PNDM incidence. All 9 patients had diabetes, liver disease and short stature. Other symptoms included neutropenia (in 8), normochromic normocytic anemia (in 7), skeletal dysplasia (in 5) multiple surgeries (in 2), and wheelchair-use (in 1 patient). 5 patients succumbed to acute fulminant hepatitis and one was rescued by liver transplant. The mutations detected were: p.W430X (c.1290G>A) in 6 members of a family and p.I650T (c.1949T>C), p.G956E (c.2867G>A), p.E524X and p.? (c.1427-?_2490þ?del) in one individual each. Two parents heterozygous for the p.W430X mutation opted for preimplantation genetic diagnosis (PGD) after they lost one child to WRS. PGD was successful and they gave birth to a healthy child. This case highlighted the importance of genetic testing for NDM patients.