Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene.

Permanent neonatal diabetes mellitus (PNDM) caused by homozygous mutations in the glucokinase gene (GCK) is rare and only eight homozygous GCK mutations have been reported so far. Heterozygous GCK mutations cause maturity-onset diabetes of the young (MODY). We report four patients with growth retardation from two separate families (with three siblings in one family and one patient in another family) presenting with persistent hyperglycaemia within the first two days of life. We found one homozygous non-sense mutation (Q98X) in GCK in three siblings from one family and a homozygous missense GCK mutation (G261R) in one patient from another family. Both mutations have been identified previously in GCK-MODY in the heterozygous state. However, this is the first study to report the homozygous forms of these mutations in PNDM. We report four novel cases of PNDM caused by homozygous GCK mutations, including a non-sense mutation in exon 3 (Q98X) and a missense mutation in exon 7 (G261R).

Bennett K ，James C ，Mutair A ，Al-Shaikh H ，Sinani A ，Hussain K ... -  《-》

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the pancreatic beta-cell sensor. Given its central role in the regulation of insulin release, it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyperglycemia and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY), characterized by mild hyperglycemia, which is present at birth, but is often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype, presenting at birth as permanent neonatal diabetes mellitus (PNDM). Several heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 195 mutations in the GCK gene have been described, in a total of 285 families. There are no common mutations and the mutations are distributed throughout the gene. Mutations that cause hypoglycemia are located in various exons in a discrete region of the protein termed the heterotropic allosteric activator site. The identification of a GCK mutation in hyper- and hypoglycemia has implications for the clinical course and clinical management of the disorder.

Gloyn AL 《-》

Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry.

Sagen JV ，Bjørkhaug L ，Molnes J ，Raeder H ，Grevle L ，Søvik O ，Molven A ，Njølstad PR ... -  《-》

A novel nonsense mutation in GCK exon 9 co-segregates with diabetes phenotype.

Knebel B ，Jacob S ，Boxberg CV ，Müller-Wieland D ，Kotzka J ... -  《EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES》

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.

Rubio-Cabezas O ，Díaz González F ，Aragonés A ，Argente J ，Campos-Barros A ... -  《-》