Identification of Two Novel Compound Heterozygous EIF2AK3 Mutations Underlying Wolcott-Rallison Syndrome in a Chinese Family.

Na Zhao,Ping Li,Yanling Yang,Han Xiao,Changxin Wu,Qiuhong Xiong

doi:10.3389/fped.2021.679646

Abstract

Objective: Wolcott–Rallison syndrome is a rare autosomal recessive inheritance disorder caused by the defectiveness of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3), which encodes the PKR-like endoplasmic reticulum kinase (PERK). Defect in EIF2AK3 results in a permanent diabetes in early infancy or newborn period, a tendency to develop skeletal fractures and other associated disorders such as severe liver and renal dysfunction, and central hypothyroidism. Two patients with Wolcott–Rallison syndrome-like manifestations in a Chinese family and family members were genetically analyzed to identify if any variations that occurred in EIF2AK3, which may cause Wolcott–Rallison syndrome.Methods: Whole-exome sequencing (WES) was performed to identify genetic variations, and Sanger sequencing was conducted to verify the identified variations in the family members with Wolcott–Rallison syndrome (WRS) clinical manifestations. Several bioinformatics tools were employed to predict the effect of EIF2AK3 variations on the protein function. The impact on PERK protein was analyzed by sequential analysis and evolution conservation study.Results: Two novel EIF2AK3 heterozygous single base variations (c.2818C>T and c.2980G>C) were detected in the proband. PERK has two functional domains: one is regulatory domain (aa 1–576), and the other is catalytic domain (aa 577–1,115). Both variations are missense mutations and locate in catalytic domain of PERK; c.2818C>T resulted in a residue substitution of proline for serine at amino acid site 940 (p.Pro940Ser), and variation c.2980G>C caused an amino acid change at position 994 from glutamic acid to glutamine (p.Glu994Gln). These novel missense variations may affect the physiological functions of PERK protein.Conclusions: Two novel compound heterozygous EIF2AK3 variations (c.2818C>T, p.Pro940Ser and c.2980G>C, p.Glu994Gln) were found in a Chinese family. The identification of the variations and verification of their pathogenicity extended the variation spectrum of EIF2AK3 variations causing Wolcott–Rallison syndrome and enriched valuable information for precise medical intervention for Wolcott–Rallison syndrome in China.

Highlights

Wolcott–Rallison syndrome (WRS, OMIM: 226980) is caused by an autosomal eukaryotic translation initiation factor 2-a kinase 3 (EIF2AK3) deficiency, associated with permanent diabetes and skeletal dysplasia in newborn period or early infancy, hepatic dysfunction, and growth retardation, which was first reported in 1972 by Wolcott and Rallison [1,2,3]
PKR-like endoplasmic reticulum kinase (PERK) acts as a major physiological effector of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress [5, 6]
Loss-of-function mutations in the EIF2AK3 gene decrease the ability of the ER to cope with stress, which results in loss of functional coordination among PERK-dependent ER chaperones responsible for controlling protein synthesis and proinsulin aggregation

Summary

Introduction

Wolcott–Rallison syndrome (WRS, OMIM: 226980) is caused by an autosomal eukaryotic translation initiation factor 2-a kinase 3 (EIF2AK3) deficiency, associated with permanent diabetes and skeletal dysplasia in newborn period or early infancy, hepatic dysfunction, and growth retardation, which was first reported in 1972 by Wolcott and Rallison [1,2,3]. Loss-of-function mutations in the EIF2AK3 gene decrease the ability of the ER to cope with stress, which results in loss of functional coordination among PERK-dependent ER chaperones responsible for controlling protein synthesis and proinsulin aggregation. These effects lead to β-cell defects and cell apoptosis, which results in permanent neonatal diabetes and epiphyseal dysplasia. Organ transplantation is a treatment for WRS; so far, three cases with organ transplantation have been reported [7,8,9], and these three patients were fully physically and socially rehabilitated

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