title: A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins.
abstract: BACKGROUND
  Permanent neonatal diabetes mellitus (PNDM) is a rare disorder, characterized by uncontrolled hyperglycemia diagnosed during the first 6 months of life. In general, PNDM has a genetic origin and most frequently it results from heterozygous mutations in KCNJ11, INS and ABCC8 genes. Homozygous or compound heterozygous inactivating mutations in GCK gene as cause of PNDM are rare. In contrast, heterozygosis for GCK inactivating mutations is frequent and results in the maturity-onset diabetes of young (MODY), manifested by a mild fasting hyperglycemia usually detected later in life. Therefore, as an autosomal recessive disorder, GCK-PNDM should be considered in families with history of glucose intolerance or MODY in first relatives, especially when consanguinity is suspected.
  
  
  RESULTS
  Here we describe two patients born from non-consanguineous parents within a family. They presented low birth weight with persistent hyperglycemia during the first month of life. Molecular analyses for KCNJ11, INS, ABCC8 did not show any mutation. GCK gene sequencing, however, revealed that both patients were compound heterozygous for two missense combined in a novel GCK-PNDM genotype. The p.Asn254His and p.Arg447Gly mutations had been inherited from their mothers and fathers, respectively, as their mothers are sisters and their fathers are brothers. Parents had been later diagnosed as having GCK-MODY.
  
  
  CONCLUSIONS
  Mutations' in silico analysis was carried out to elucidate the role of the amino acid changes on the enzyme structure. Both p.Asn254His and p.Arg447Gly mutations appeared to be quite damaging. This is the first report of GCK-PNDM in a Brazilian family.
authors.affiliation: Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP Brazil ; Center of Molecular Biology and Genetic Engineering (CBMEG), UNICAMP, Campinas, Brazil ; Center for Investigation in Pediatrics (CIPED), FCM, UNICAMP, Campinas, Brazil.
authors.forename: Adriana Mangue
authors.identifier: 0000-0003-0061-8217
authors.initials: AM
authors.lastname: Esquiaveto-Aun
authors.affiliation: Center of Molecular Biology and Genetic Engineering (CBMEG), UNICAMP, Campinas, Brazil.
authors.forename: Maricilda Palandi
authors.initials: MP
authors.lastname: De Mello
authors.affiliation: Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP Brazil.
authors.forename: Maria Fernanda Vanti Macedo
authors.initials: MF
authors.lastname: Paulino
authors.affiliation: Division of Endocrinology, Department of Clinical Medicine, FCM, UNICAMP, Campinas, Brazil.
authors.forename: Walter José
authors.initials: WJ
authors.lastname: Minicucci
authors.affiliation: Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP Brazil ; Center for Investigation in Pediatrics (CIPED), FCM, UNICAMP, Campinas, Brazil.
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra-Júnior
authors.affiliation: Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas (UNICAMP), Campinas, SP Brazil ; Center for Investigation in Pediatrics (CIPED), FCM, UNICAMP, Campinas, Brazil.
authors.forename: Sofia Helena Valente
authors.initials: SH
authors.lastname: De Lemos-Marini
keywords: GCK; Glucokinase; MODY; PNDM; Permanent neonatal diabetes mellitus