Abstract
BackgroundWolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene.MethodsGenetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry.ResultsThe first cases in Hungary, − two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11– intron 11–12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver.ConclusionsThe novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.
Highlights
Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families
The poor prognosis of WRS is associated with liver failure triggered by endoplasmic reticulum stressors like viral, bacterial infections, and hypoglycemia; later the outcome is determined by the possible complications of insulin therapy and hepatic injury
Based on the data of the Human Gene Mutation Database (HGMD), 88 different genetic alterations have been described in the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene (Fig. 7) (HGMD® home page: www.hgmd.cf.ac.uk [20]) and majority of the cases (n = 52) represent single nucleotide substitutions (Fig. 7a), of which 24 result in STOP codon and 28 in amino acid change
Summary
Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. Wolcott-Rallison syndrome (WRS, OMIM 226980) is a rare autosomal recessive disorder, first described in 1972 [1]. The leading clinical symptom of the disease is persistent neonatal diabetes mellitus that requires insulin treatment. Diabetes develops typically not later than 6 months after birth, but delayed cases have been described [1,2,3,4,5]. Sporadic cases were described with hypothyreoidism [7], exocrine pancreas insufficiency [8, 9], skin [1] or central nervous system abnormalities (microcephaly, pachygyria, mental retardation) [10,11,12,13]
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