Pål R. Njølstad

Hyperexcitability to sulphonylurea in MODY3

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A missense mutation, Val62Ala, in the glucokinase gene in a Norwegian family with maturity-onset diabetes of the young

Maturity‐onset diabetes of the young (MODY) is a form of diabetes mellitus characterized by autosomal dominant inheritance, onset usually before 25 y of age and a primary defect in glucose‐stimulated insulin secretion. It is a heterogeneous disorder both with respect to aetiology and clinical features. Mutations in the genes encoding the glycolytic enzyme glucokinase, the liver‐enriched transcription factors, hepatocyte nuclear factor‐1a (HNF‐1a), HNF‐1b and HNF‐4a, and the transcription factor, insulin promoter factor‐1 (IPF‐1) have all been associated with MODY. Here, we report a family, Norway‐2 (N2), characterized by the presence of a mild, complication‐free form of diabetes with autosomal dominant inheritance. Sequencing of the glucokinase gene in the proband revealed a T‐to‐C mutation in codon 62 which resulted in a valine‐to‐alanine substitution, designated Val62Ala (V62A). The V62A mutation, which has not been previously reported, cosegregated with diabetes in the N2 family. The results presented here indicate that the glucokinase form of MODY occurs in Norway. Moreover, screening the glucokinase gene for mutations in other families with clinical features similar to those of the N2 family could lead to improved treatment for patients with this form of diabetes.

Genetic variants of hepatocyte nuclear factor-1β in Chinese young-onset diabetic patients with nephropathy

In Hong Kong, the prevalence of diabetes is estimated to be 2% in the young population. In the diabetic population, 30% of patients have diagnosis before the age of 40 years. Besides, 30% of young diabetic patients have varying degrees of albuminuria. Mutations in the gene encoding the hepatocyte nuclear factor (HNF)-1beta are associated with a subtype of maturity-onset diabetes of the young (MODY 5) characterized by urogenital abnormalities. We examined 74 unrelated Chinese subjects with young-onset diabetes complicated by nephropathy for variants in this gene. The HNF-1beta gene was screened by direct sequencing and the functional properties of wild-type and mutant proteins were analyzed by transactivation analysis.A novel variant in exon 3 (E260D) was found in one patient. Extended family analysis revealed four other siblings carrying this variant. One subject had diabetes and another had impaired glucose tolerance. Another sibling had microalbuminuria but normal glucose tolerance. Transfection studies showed insignificant differences in transactivation ability between wild-type and mutated HNF-1beta. A silent polymorphism Q378Q was identified in another unrelated subject. These results suggest genetic variants in HNF-1beta are not a common cause of young-onset diabetes or diabetic nephropathy in Chinese, but may modify disease manifestation and progression. Other potential candidate genes should be looked for to account for the high prevalence of young-onset diabetes and nephropathy in this population.

The Molecular Genetics and Pathophysiology of Congenital Hyperinsulinism Caused by Short-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Deficiency of the metabolic enzyme short-chain 3-hydroxyacyl-CoA (SCHAD) is a rare autosomal recessive form of congenital hyperinsulinism of infancy caused by mutations in the HADH