Two novel mutations in the EIF2AK3 gene in children with Wolcott-Rallison syndrome

Abstract

Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, epiphyseal dysplasia, and other multisystemic clinical manifestations. We described two novel mutations in the EIF2AK3 gene in two consanguineous families with WRS from Brazil and Morocco. We have observed in case 1 a homozygous C > T replacement at base pair c.1192 at exon 7, generating a stop codon at position 398 (Gln398Stop). Both of his parents were found to be heterozygous for the mutation. We detected in both parents of case 2, a deceased Moroccan girl, a duplication of base pair c.851A at exon 5 (c.851dupA) leading to a frameshift and a stop codon at position 285 (p.Pro285AlafsX3). Both cases 1 and 2 had neonatal diabetes mellitus, multiple epiphyseal dysplasia, and growth delay, and presented episodes of acute hepatic dysfunction. Case 1 presented central hypothyroidism, developmental delay, and mild mental retardation. Case 2 presented a fatal episode of acute renal failure. The clinical phenotype associated with the syndrome can be variable, but a combination of infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, and hepatic and/or renal dysfunction is the mainstay of diagnosis.

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

“…This has been corroborated by several recent reports of non-sense mutations found in different exons of the EIF2AK3 gene leading to protein truncation, and therefore WRS [10,13,15].…”

“…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.…”

The eIF2α kinase PERK limits the expression of hippocampal metabotropic glutamate receptor-dependent long-term depression

“…Global deletion of PERK in mice impairs development of the skeletal system, postnatal growth, and pancreatic viability (Harding et al 2001;Zhang et al 2002;Wei et al 2008). In humans, mutations of the PERK gene (EIF2AK3) cause Wolcott-Rallison syndrome (WRS), a rare autosomal recessive disorder characterized by early onset diabetes, liver dysfunction, and pancreas insufficiency (Delepine et al 2000;Rubio-Cabezas et al 2009;Julier and Nicolino 2010) and, in some cases, mental retardation (Thornton et al 1997;Delepine et al 2000;Senee et al 2004;Reis et al 2011). Together, these analyses suggest that PERK functions as a critical modulator of a number of cellular processes requiring precise translational control.…”

A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child

“…EIF2AK3 encodes a transmembrane enzyme that localized to endoplasmic reticulum and phosphorylates the alpha subunit of eukaryotic initiation factor 2 (EIF2). Mutations in this gene are associated with Wolcott-Rallison syndrome (OMIM: 226980), a rare autosomal recessive disorder characterized by permanent neonatal diabetes or early childhood insulindependent diabetes mellitus type 1, epiphyseal dysplasia, hepatic and kidney dysfunction, and cardiac abnormalities (Perego et al 2004;Jahnavi et al 2014;Biason-Lauber et al 2002;Reis et al 2011). Our patient does not present with any of these symptoms.…”