Six Mutations in the Glucokinase Gene Identified in MODY by Using a Nonradioactive Sensitive Screening Technique
- Jörg Hager,
- Hélène Blanché,
- Fang Sun,
- Nathalie Vionnet Martine Vaxillaire,
- Wolfgang Poller,
- Daniel Cohen,
- Paul Czernichow,
- Gilberto Velho,
- Jean-Jacques Robert,
- Nadine Cohen and
- Philippe Froguel
- Human Polymorphism Study Center (C.E.P.H.-Fondation Jean Dausset); INSERM U-30, Hüpital Necker-Enfants Malades Paris INSERM U-358, Hüpital Saint-Louis, Endocrinology, Department, Hopital Robert Debre Paris, France Department of Biochemistry and Pathobiochemistry, Medical University Clinic, University of Wiirzburg Germany
- Address correspondence and reprint requests to Dr. Philippe Froguel, Centre d'Etude du Polymorphisme Humain (CEPH), 27 rue Juliette Dodu, 75010 Paris, France.
We have reported that 56% of French families with maturity-onset diabetes of the young (MODY) carry a mutation in the glucokinase gene (GCK). Therefore, we have established a quick and sensitive nonradioactive technique (with the PhastSystemTM based on single-strand conformation polymorphism [SSCP] analysis) to routinely screen the 12 exons of GCK for mutations. We have studied GCK in 12 young hyperglycemic patients with a strong family history of type II diabetes. SSCP variants were observed in 6 of those 12 patients (50%), which cosegregated with diabetes in five families where DNA from additional members was available. Direct sequencing identified a 10-bp (base pair) deletion in exon 3; a 33-bp deletion at the exon 5/intron 5 junction, including the two consensus bases (GT) of the donor splice site; a nonsense mutation in exon 5 (Arg186 → Stop) in a Black-African family, which has been identified previously in a Caucasian family; and three missense mutations: Thr209 → Met209 in exon 6, Gly261 → Glu261 in exon 7, and Arg36 → Trp36 in exon 2. The missense mut ation in exon 2 was found only in the second and third generation of the tested family but not in the first. To our knowledge, this is the first time that a de novo mutation of GCK is reported within a family. All six families carrying a mutation in GCK were typical MODY and most of their affected members had a mild form of diabetes. This nonradioactive SSCP technique may be useful to routinely diagnose glucokinase deficiency, which is an important cause of hyperglycemia among young type II diabetic patients.
- Received October 11, 1993.
- Revision received January 13, 1994.
- Accepted January 13, 1994.
- Copyright © 1994 by the American Diabetes Association