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Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3
  1. S Brickwood1,
  2. D T Bonthron2,
  3. L I Al-Gazali3,
  4. K Piper1,
  5. T Hearn1,
  6. D I Wilson1,
  7. N A Hanley1
  1. 1Division of Human Genetics, Southampton University, Southampton, UK
  2. 2Molecular Medicine Unit, University of Leeds, St James’s University Hospital, Leeds, UK
  3. 3Department of Paediatrics, FMHS, UAE University, Al Ain, UAE
  1. Correspondence to:
 Dr Neil A Hanley, Division of Human Genetics, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK;

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Wolcott-Rallison syndrome (OMIM 226980) is a rare autosomal recessive disorder characterised by permanent insulin requiring diabetes developing in the newborn period or early infancy, an early tendency to skeletal fractures, and spondyloepiphyseal dysplasia.1–8 The syndrome results from mutations in the gene encoding the eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3, also called PERK or PEK).9 This enzyme phosphorylates EIF2A at Ser51 to regulate the synthesis of unfolded proteins in the endoplasmic reticulum.10 Targeted disruption of the Eif2ak3 gene in mice also causes diabetes because of the accumulation of unfolded proteins triggering β cell apoptosis.1112 Although these murine models have provided significant insight into the pathogenesis of Wolcott-Rallison syndrome, only three human cases have been characterised genetically.89 Here, we report genetic analysis of two further cases, and demonstrate new features of the expression pattern of human EIF2AK3 that offer possible explanations for important clinical features of the syndrome that are not apparent in the transgenic mouse models.


Primers were designed to amplify all EIF2AK3 exons and splice site sequences from genomic DNA (table 1). Sequences were amplified by 35 cycles of polymerase chain reaction (PCR) using a proof-reading DNA polymerase in 50 μl reactions and purified (Qiaquick, Qiagen, Crawley, Sussex, UK). Products were sequenced using the BigDye terminator cycle sequencing kit according to the manufacturer’s instructions (Perkin-Elmer, Foster City, California, USA) and an ABI 377 sequencer (Applied Biosystems, city, county, UK). Sequences were compared to the published EIF2AK3 gene by BLAST analysis ( For potential mutations, the PCR and sequencing was repeated to confirm the result. Restriction digest analysis was also used to confirm the mutation in case 2, where the G→A substitution destroyed an HphI site.

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Table 1

Primers used to amplify the EIF2AK3 gene

Optimal conditions were determined for …

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