IDENTIFICATION OF 14 NEW GLUCOKINASE MUTATIONS AND DESCRIPTION OF THECLINICAL PROFILE OF 42 MODY-2 FAMILIES

Mutations in glucokinase are associated with defects in insulin secret ion and hepatic glycogen synthesis resulting in mild chronic hyperglyc aemia, impaired glucose tolerance or diabetes mellitus. We screened me mbers of 35 families with features of maturity-onset diabetes of the y oung for mutations in the glucokinase gene and found 16 different muta tions. They included 14 new mutations in the glucokinase gene: 9 misse nse mutations (A53S, G80A, H137R, T168P, M210T, C213R, V226M, S336L an d V367M); 2 nonsense mutations (E248X and S360X); a deletion of one nu cleotide resulting in a frameshift (V401del1); a substitution of a con served nucleotide at a splice acceptor site (L122-1G --> T); and a 10 base pair deletion that removed the GT of the splice donor site and th e following eight nucleotides (K161 + 2del10). In addition, we found t wo previously identified mutations: R186X and G261R. Study of 260 subj ects with glucokinase-deficient hyperglycaemia from 42 families with 3 6 different GCK mutations made it possible to define the clinical prof ile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM) . Hyperglycaemia due to glucokinase deficiency is often mild (fewer th an 50% of subjects have overt diabetes) and is evident during the earl y years of life. Despite the long duration of hyperglycaemia, glucokin ase-deficient subjects have a low prevalence of micro- and macro-vascu lar complications of diabetes. Obesity, arterial hypertension and dysl ipidaemia are also uncommon in this form of NIDDM.