title: EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Advanced Centre for Genomics of Type 2 Diabetes and Dr. Mohan's Diabetes Specialities Centre, WHO Collaborating Centre for Non Communicable Diseases Prevention and Control, IDF Centre of Education, Chennai, Tamil Nadu, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Jahnavi
authors.forename: Varadarajan
authors.initials: V
authors.lastname: Poovazhagi
authors.forename: Sekar
authors.initials: S
authors.lastname: Kanthimathi
authors.forename: Vijay
authors.initials: V
authors.lastname: Gayathri
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Mohan
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Radha
mesh_terms: D019943:Amino Acid Substitution; D003409:Congenital Hypothyroidism / Q000209:etiology / Q000503:physiopathology; D003241:Consanguinity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D004838:Epiphyses / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D048550:Hepatic Insufficiency / Q000209:etiology / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D010375:Pedigree; D017354:Point Mutation; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000503:physiopathology; D012720:Severity of Illness Index; D019892:eIF-2 Kinase / Q000235:genetics*
chemical_list: C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: EIF2AK3; PERK; PNDM; WRS