HIGH PREVALENCE OF A MISSENSE MUTATION OF THE GLUCOKINASE GENE IN GESTATIONAL DIABETIC-PATIENTS DUE TO A FOUNDER-EFFECT IN A LOCAL-POPULATION

A high proportion of the female patients who are members of maturity o nset diabetes of the young (MODY) pedigrees, and whose diabetes mellit us is due to a glucokinase mutation, originally presented with gestati onal diabetes. To establish whether glucokinase mutations could be a c ommon cause of gestational diabetes, we studied 50 subjects who presen ted with gestational diabetes and on follow-up had hyperglycaemia (5.5 -10.0 mmol/l). Screening for glucokinase mutations using single-strand ed conformational polymorphism (SSCP) analysis detected a missense mut ation at position 299 (Gly(299)-->Arg) in three subjects. As two pedig rees in the Oxford area had the same glucokinase mutation, we suspecte d the role of a founder-effect, and carried out pedigree extension, ha plotype construction (using microsatellite markers GCK1 and GCK2) and mutation screening of at-risk subjects from the same geographical area . One of the gestational diabetic subjects was found to be related to one of the previous pedigrees via her paternal grandmother. Subjects w ith the mutation were found to have the Z + 4/2 (GCK1/ GCK2) haplotype , suggesting that the observed high prevalence of the Gly(299)-->Arg g lucokinase mutation in the Oxford region was due to a founder-effect. Since glucokinase mutations predominantly induce subclinical hyperglyc aemia, it is likely that in the locality of other pedigrees there will be undiagnosed subjects with the same glucokinase mutation, which rem ains undetected unless pregnancy occurs.