title: Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.
abstract: Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.
authors.affiliation: Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Rubio-Cabezas
authors.forename: F
authors.initials: F
authors.lastname: Díaz González
authors.forename: A
authors.initials: A
authors.lastname: Aragonés
authors.forename: J
authors.initials: J
authors.lastname: Argente
authors.forename: A
authors.initials: A
authors.lastname: Campos-Barros
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D018389:Codon, Nonsense; D003241:Consanguinity; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics*; D004927:Escherichia coli Infections / Q000150:complications / Q000175:diagnosis; D005260:Female; D005941:Glucokinase / Q000172:deficiency* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics; D007231:Infant, Newborn; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D010375:Pedigree
chemical_list: D000900:Anti-Bacterial Agents; D018389:Codon, Nonsense; D007328:Insulin; D005941:Glucokinase