Six Mutations in the Glucokinase Gene Identified in MODY by Using a Nonradioactive Sensitive Screening Technique

  1. Philippe Froguel
  1. 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
  1. Address correspondence and reprint requests to Dr. Philippe Froguel, Centre d'Etude du Polymorphisme Humain (CEPH), 27 rue Juliette Dodu, 75010 Paris, France.

Abstract

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.
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