LINKAGE ANALYSIS AND MOLECULAR SCANNING OF GLUCOKINASE GENE IN NIDDM FAMILIES

Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to th e development of late-onset NIDDM, linkage analyses between DNA polymo rphisms at the glucokinase locus and NIDDM were performed in 79 multig enerational French families. in addition, all exons and the islet prom oter region of glucokinase gene from 1 affected member from each famil y as well as from 17 unrelated women with previous gestational diabete s were amplified by polymerase chain reaction and screened for mutatio ns by single-strand conformational polymorphism and DNA sequencing. Li nkage of glucokinase and NIDDM was significantly rejected under all mo dels tested. However, in 1 family, the lod score was 2.30, and we foun d a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase w as found in the 79 NIDDM families. We identified a missense mutation ( TGG257 --> CGG257) in exon 7 of glucokinase gene from 1 of 17 women wi th gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabe tes of the young, as 4 younger members, carrying this mutation, were s ubsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of on set NIDDM. Diabetic families with mutations in glucokinase must be car efully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals dia betes in women carrying a glucokinase defect.