title: Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique.
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 PhastSystem 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 mutation 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.
authors.affiliation: Human Polymorphism Study Center (C.E.P.H.-Fondation Jean Dausset, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Hager
authors.forename: H
authors.initials: H
authors.lastname: Blanché
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.forename: N V
authors.initials: NV
authors.lastname: Vaxillaire
authors.forename: W
authors.initials: W
authors.lastname: Poller
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.forename: P
authors.initials: P
authors.lastname: Czernichow
authors.forename: G
authors.initials: G
authors.lastname: Velho
authors.forename: J J
authors.initials: JJ
authors.lastname: Robert
authors.forename: N
authors.initials: N
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000367:Age Factors; D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D005941:Glucokinase / Q000235:genetics*; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D012680:Sensitivity and Specificity
chemical_list: D003062:Codon; D005941:Glucokinase