Wolcott‐Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature

Abstract

Background: Wolcott‐Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. Aims: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow‐up details on our first family including the longest surviving child. Methods: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott‐Rallison syndrome. Results: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4‐base pair deletion (nt 3021–3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy‐ segment of the catalytic domain. Conclusions: Wolcott‐Rallison syndrome causes early‐onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

“…When these mechanisms do not remedy the stress situation, apoptosis is initiated. Since a number of articles have recently reported that ER stress may be implicated in beta cell dysfunction and death in diabetes [10][11][12][13][14][15][16][19][20][21][22][23][24][25][26], in the present study we evaluated features of ER function/dysfunction in human beta cells from type 2 diabetic organ donors. First, we confirmed that diabetic beta cells have functional and survival defects, as previously shown by us and others [27,28,[35][36][37][38].…”

“…In addition, NEFAs cause induction of specific ER stress markers such as X-box binding protein 1 (XBP-1, also known as XBP1), immunoglobulin heavy chain binding protein (BiP, also known as heat shock 70 kDa protein 5 [glucose-regulated protein, 78 kDa] [HSPA5]), activating transcription factor 4 and 6 (ATF4 and ATF6), and CHOP (also known as damage-inducible transcript 3 [DDIT3]) in INS-1E cells, while cytokines cause a decrease in ER calcium and severe ER stress in INS-1E and primary beta cells [10,11,13,[19][20][21]. In vivo, a mutation in eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also known as PERK) impairs the development of a normal UPR and causes neonatal diabetes in Wolcott-Rallison syndrome [22]. Increased beta cell sensitivity to ER stress and apoptosis are also observed in the Perk-deficient mouse and in mice homozygous for a eukaryotic translation initiation factor 2a (Eif2a) serine 51 to alanine substitution [23].…”

Nck in a Complex Containing the Catalytic Subunit of Protein Phosphatase 1 Regulates Eukaryotic Initiation Factor 2α Signaling and Cell Survival to Endoplasmic Reticulum Stress

“…Functional defects in some players of the UPR have been associated with metabolic or neurologic pathological manifestations. For example, patients affected by the Wolcott-Rallison syndrome, which results in neonatal insulin-dependent diabetes, show mutations in the PERK/EIF2AK3 gene (32). Similarly, mice lacking expression of PERK (33) or harboring an eIF2␣ that escapes phosphorylation (eIF2␣ Ser 51 for Ala) (18) further illustrate a central role for PERK and eIF2␣ phosphorylation in pancreatic ␤-cells function.…”

Identification of Novel Mutation in EIF2AK3 Gene as a Causal Variant in a Family With Rare Disease

“…So far, several mutations have been reported in this gene which led to the onset of WRS [5,7,8]. These mutations are non-sense, frameshift, missense, and splice site mutations which have been observed in both homozygous and compound heterozygous state [4,[8][9][10][11][12][13][14][15]. Here we report a novel non-sense mutation in EIF2AK3 gene in an Iranian girl.…”