EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome

Pediatr Diabetes. 2014 Jun;15(4):313-8. doi: 10.1111/pedi.12089. Epub 2013 Oct 30.


Objective: This study describes the clinical and genetic evaluation of permanent neonatal diabetes due to Wolcott-Rallison syndrome (WRS) in south Indian consanguineous families. We aimed to evaluate the genetic basis of the disease in eight children with WRS from five South Indian families.

Patients and methods: We studied eight children who presented with permanent neonatal diabetes from five South Indian families. Follow up clinical evaluation revealed features (like liver disease, skeletal dysplasia, and thyroid dysfunction) suggestive of WRS. All the coding exons along with splice sites of KCNJ11, ABCC8, INS, GCK and EIF2AK3 genes were sequenced in all the probands.

Results: Two novel homozygous mutations (Trp658Ser, c.3150+1G>T) and one known homozygous mutation (Arg1065*, c.3193C>T) in EIF2AK3 gene were identified in children with WRS. Mutation Arg1065*was identified in four children.

Conclusions: Our results in these families show that the mutations in homozygous state are likely to be causative. We suggest the screening for EIF2AK3 gene mutations as WRS is now recognized as the most frequent cause of neonatal diabetes in children with consanguineous parents. As the mode of inheritance is recessive, screening for genetic mutations becomes important to aid in risk prediction and clinical management.

Keywords: EIF2AK3; PERK; PNDM; WRS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Congenital Hypothyroidism / etiology
  • Congenital Hypothyroidism / physiopathology
  • Consanguinity
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / mortality
  • Diabetes Mellitus, Type 1 / physiopathology
  • Epiphyses / abnormalities*
  • Epiphyses / physiopathology
  • Female
  • Follow-Up Studies
  • Genetic Association Studies
  • Hepatic Insufficiency / etiology
  • Hepatic Insufficiency / physiopathology
  • Homozygote
  • Humans
  • India
  • Infant
  • Infant, Newborn
  • Male
  • Mutation*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / mortality
  • Osteochondrodysplasias / physiopathology
  • Pedigree
  • Point Mutation
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / physiopathology
  • Severity of Illness Index
  • eIF-2 Kinase / genetics*


  • EIF2AK3 protein, human
  • eIF-2 Kinase

Supplementary concepts

  • Wolcott-Rallison syndrome