A Novel Nonsense Mutation in GCK Exon 9 Co-Segregates with Diabetes Phenotype

Abstract

Maturity-onset diabetes of the young is an autosomal dominant form of non-insulin dependent diabetes mellitus and is caused by mutations in at least six different genes. In the most common forms, i.e. MODY2 and MODY3, the glucokinase (GCK) and the hepatocyte nuclear factor (HNF)-1α gene is affected, respectively. We have screened the GCK gene and HNF-1α gene by direct sequencing in three German families with early onset type-2-diabetes, possibly MODY. Next to known polymorphisms we have identified two novel intronic insertions in GCK and a novel non-sense mutation in exon 9 (C364 X). The latter mutation has an autosomal dominant inheritance pattern. Accordingly, this novel mutation segregates with diabetes phenotype in this family.

Hepatocyte nuclear factor - glucokinase - maturity-onset diabetes of the young - mutation - molecular diagnosis

References

• 1 Bell G I, Polonsky K S. Diabetes mellitus and genetically programmed defects in b-cell function.  Nature. 2001;  414 788-791
• 2 Bingham C, Nicholls A J, Hatterslay A T. Heterogeneity in the clinical course of patients with type 2 diabetes on dialysis - the need for different preventative strategies.  Diabet Med. 2000;  17 685-686
• 3 Byrne M M, Sturis J, Clement K, Vionnet N, Pueyo M E, Stoffel M, Takeda J, Passa P, Cohen D, Bell G I. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.  J Clin Invest. 1994;  93 1120-1130
• 4 Ellard S. Hepatocyte nuclear factor alpha (HNF)-1α mutations in maturity-onset diabetes of the young.  Human Mutation. 2000;  16 377-385
• 5 Frougel P, Vaxillaire M, Sun F, Vehlo G, Zouali H, Butel M O, Lesage S, Vionnet N, Clement K, Fougerousse F, Tanizawa Y, Weissenbach J, Beckmann J S, Lathrop G M, Passa P, Permutt M A, Cohen D. Close linkage of glucokinase locus on chromosome 7 p to early-onset non-insulin-dependant diabetes mellitus.  Nature. 1992;  356 162-164
• 6 Frougel P, Zouali H, Vionnet N, Vehlo N, Vaxillaire M, Sun F, Leasage S, Stoffel M, Takeda J, Passa P, Permutt M A, Beckman J S, Bell G I, Cohen D. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus.  N Engl J Med. 1993;  328 697-702
• 7 Gidh-Jain M, Takeda J, Xu L Z, Lange A J, Vinonnet N, Stoffel M, Frougel P, Vehlo G, Sun F, Cohen D, Patel P, Lo Y-MD, Hatterslay A T, Luthman H, Wedell A, Charles Rr St, Harrison R W, Weber I T, Bell G I, Pilkis S J. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships.  Proc Natl Acad Sci USA. 1993;  90 1932-1936
• 8 Gloyn A L. Glucokinase (GCK) mutations in hyper and hypoglycemia: Maturity-onset-diabetes of the young, permanent neonatal diabetes & hyperinsulinaemia of infancy.  Human Mutation. 2003;  22 353-362
• 9 Hatterslay A T. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.  Diabetic Medicine. 1998;  15 15-24
• 10 Horikawa Iwasaki Hara Y N, Furuta H, Hinokio Y, Cockburn, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahar T, Iwamoto Y, Bell G I. Mutation in hepatocyte nuclear factor beta gene (TCF2) associated with MODY.  Nature Genetics. 1997;  17 384-385
• 11 Malecki M T, Jhala U S, Antonellis A, Fields L, Doria A, Orban T, Saad M, Warram J H, Montmini M, Krolewski A S. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus.  Nature Genetics. 1999;  23 323-328
• 12 Matschinsky F M. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics.  Diabetes. 2002;  51 (Suppl 3) S394-S404
• 13 Ng M C, Li J K, So W Y, Critchley J A, Cockram C S, Bell G I, Chan J C. Nature or nurture: an insightful illustration from a Chinese family with hepatocyte nuclear factor-1 alpha diabetes (MODY3).  Diabetologia. 2000;  43 816-818
• 14 Sagan J V, Nojlstad P R, Sovik O. Reduced prevalence of late diabetic complications in MODY 3 with early diagnosis.  Diabetic Medicine. 2002;  19 697-698
• 15 Stoffel M, Patel P, Lo Y M, Hatterslay A T, Lucassen A M, Page R, Bell J I, Bell G I, Turner R C, Wainscoat J S. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late onset diabetes.  Nature Genetics. 1992;  2 153-156
• 16 Stoffers D A, Ferrer J, Clarce W L, Habener J F. Early-onset type-II Diabetes melliuts (MODY 4) linked to IPF1.  Nature Genetics. 1997;  17 138-139
• 17 Thomson K L, Gloyn A L, Colclough K, Batten M, Allen L IS, Beards F, Hatterslay A T, Ellard S. Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young.  Human Mutation. 2003;  22 417
• 18 Velho G, Vaxillaire M, Bocchio V, Charpentier G, Froguel P. Diabetes complications in NIDDM kindreds linked to the MODY 3 locus on chromosome 12 q.  Diabetes Care. 1996;  19 915-919
• 19 Yamagata K, Furuta H, Oda N, Kaisaki P J, Menzel S, Coy N J, Frajans S S, Signiorini S, Stoffel M, Bell G I. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY 1).  Nature. 1996 a;  384 458-460
• 20 Yamagata K, Oda N, Kaisaki P J, Menzel S, Furuta H, Vaxillaire M, Southam L, Lathrop G M, Boriraj V V, Chen X, Cox N J, Oda Y, Yano H, Le Beau M M, Yamada S, Nishigori H, Takeda J, Frajans S S, Hatterslay A T, Iwasaki N, Pedersen O, Polonski K S, TurnerRC, Vehlo G, Chevre J-C, Frougel P, Bell G I. Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3).  Nature. 1996 b;  384 455-458