Identifizierung neuer Mutationen im Glukokinase-Gen (MODY2) und HNF1alpha-Gen (MODY3)

Zusammenfassung

Maturity-onset diabetes of the young (MODY) ist eine autosomal dominante Form des nicht insulinabhängigen Diabetes. Es werden sechs klinisch und genetisch unterschiedliche Formen unterschieden. Die MODY Formen mit der höchsten Prävalenz in der deutschen Population, MODY2 und MODY3, werden durch Mutationen in den Genen der Glukokinase (GCK) (MODY2) bzw. des Transkriptionsfaktors hepatocyte nuclear factor (HNF)-1α (MODY3) verursacht. Wir haben Familien mit frühem Auftreten von Diabetes mellitus, und klinischem Verdacht auf MODY durch direkte Sequenzierung des GCK- und HNF-1α-Gens untersucht. Neben bekannten Polymorphismen und bereits in anderen Familien identifizierten Mutationen haben wir in einzelnen Familien fünf neue Mutationen identifiziert.

Abstract

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of non insulin dependent diabetes. Six clinical and genetically different forms are known. The MODY forms with the highest prevalence in German population, MODY2 and MODY3, are caused by mutations in the genes for glucokinase (GCK) (MODY2) and the transcription factor hepatocyte nuclear factor (HNF)-1α (MODY3). In families with early onset diabetes mellitus and suspected MODY we investigated GCK and HNF-1α gene by direct sequencing. Next to known polymorphisms and mutations identified in different families, we identified five novel mutations.

hepatocyte nuclear factor - Glucokinase - maturity-onset diabetes of the young - molekulare Diagnostik

hepatocyte nuclear factor - Glucokinase - maturity-onset diabetes of the young - molecular diagnostic

Literatur

• 1 Hattersley A T, Beards F, Ballantyne E et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight.  Nat Genet. 1998;  19 268-270
• 2 Hattersley A T. Molecular genetics goes to the diabetes clinic.  Clin Med. 2005;  5 476-481
• 3 Fajans S S, Bell G I, Polonsky K S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.  N Engl J Med. 2001;  345 971-980
• 4 Velho G, Robert J J. Maturity-onset diabetes of the young (mody): genetic and clinical characteristics.  Horm Res. 2002;  57 29-33
• 5 Gloyn A L. Glucokinase (GCK) Mutations in hyper- and hypoglycemia: Maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.  Human Mutation. 2003;  22 353-362
• 6 Niølstad P R, Søvik O, Cuesta-Munoz A. Neonatal diabetes mellitus due to complete Glucokinase deficiency.  N Engl J Med. 2001;  344 1588-1592
• 7 Stoffel M, Duncan S A. The maturity diabetes of the young (MODY1) transcription factor HNF 4α regulates expression of genes required for glucose transport and metabolism.  Proc Natl Acad Sci USA. 1997;  94 13209-13214
• 8 Wang H, Maechler P, Anitnozzi P A et al. Hepatocyte nuclear factor 4α regulates the expression of pancreatic beta cell genes implicated in glucose metabolism and nutrient-induced insulin secretion.  J Biol Chem. 2000;  275 35953-35959
• 9 Fajans S S. MODY: a model for understanding the pathogenesis and natural history of type II diabetes.  Horm Metab Res. 1987;  19 519-599
• 10 Fajans S S, Bell G I, Bowden D H et al. Maturity - onset diabetes of the young.  Life Sci. 1994;  55 413-422
• 11 Fajans S S, Brown M B. Administration of sulfonureas can increase glucose-induced insulin secretion for decades in patients with maturity-onset diabetes of the young.  Diabetes Care. 1993;  16 1254-1261
• 12 Frayling T M, Bulman M P, Ellard S et al. Mutations in hepatocyte nuclear factor 1α gene are a common cause of maturity onset diabetes of the young in the UK.  Diabetes. 1997;  46 720-725
• 13 Herman W H, Fajans S S, Ortiz F J et al. Abnormal insulin secretion not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree.  Diabetes. 1994;  43 40-46
• 14 Byrne M M, Sturis J, Fajans S S et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20.  Diabetes. 1995;  44 699-704
• 15 Byrne M M, Sturis J, Menzel S et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic sybjects with a mutation in the diabetes susceptibility gene MODY3 on chromosome 12.  Diabetes. 1996;  45 1503-1510
• 16 Letho M, Tuomi T, Mahtanti M M et al. Characterization of the MODY3 phenotype: early-onset diabetes caused by an insulin secretion defect.  J Clin Invest. 1997;  99 582-591
• 17 Odom D T, Zizlsperger N, Gordon D B et al. Control of pancreas and liver gene expression by hnf transcription factors.  Science. 2004;  303 1378-1381
• 18 Wright N M, Metzger D L, Borowitz S M. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis.  Am J Dis Child. 1993;  147 607-609
• 19 Clocquet A R, Eagan J M, Stoffers D A et al. Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene).  Diabetes. 2000;  49 1856-1864
• 20 Naya F J, Huang H P, Qui Y et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BEAT2 / NeuroD1 deficient mice.  Genes Dev. 1997;  11 2323-2334
• 21 Maleki M T, Jhala U S, Antonellis A et al. Mutations in NeuroD1 are associated with the developement of type 2 diabetes mellitus.  Nat Genet. 1999;  23 323-328
• 22 Knebel B, Jacob S, Boxberg C V et al. A novel nonsense mutation in GCK exon 9 co-segregates with diabetes phenotype.  Exp Clin Endocrinol Diabetes. 2004;  112 298-301
• 23 Frayling T M, Hattersley A T. The role of genetic susceptibility in the association of low birth weight with type 2 diabetes.  Br Med Bull. 2001;  60 89-101
• 24 Owen K, Hattersley A T. Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization.  Best Pract Res Clin Endocrinol Metab. 2001;  15 309-323
• 25 Velho G, Froguel P. Genetic, metabolic and clinical characteristics of maturity onset diabetes of the young.  Eur J Endocrinol. 1998;  138 233-239
• 26 Glucksmann M A, Lehto M, Tayber O et al. Novel mutations and a mutational hotspot in the MODY3 gene.  . 1997;  46 1081-1086
• 27 Massa O, Meschi F, Cuesta-Munoz A et al. Italian Society of Paediatic Endocrinology and Diabetes (SIEDP). High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP).  Diabetologia. 2001;  44 898-905
• 28 Ziemssen F, Bellanné-Chantelot C, Osterhoff M et al. Molecular genetics of MODY in Germany.  Diabetologia. 1999;  42 121-123 , To: Lindner T, Cockburn BN, Bell GI. Diabetologia 2002; 45: 286-287
• 29 Miller S P, Anand G R, Karschnia E J et al. Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.  Diabetes. 1999;  48 1645-1651
• 30 Hager J, Blanché H, Sun F, Vaxillaire M et al. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique.  Diabetes. 1994;  43 730-733
• 31 Mantovani V, Salardi S, Cerreta V et al. Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young.  Hum Mutat. 2003;  22 338
• 32 Thomson K L, Gloyn A L, Colclough K et al. Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).  Hum Mutat. 2003;  22 417
• 33 Pruhova S, Ek J, Lebl J et al. Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha.  Diabetologia. 2003;  46 291-295
• 34 Bell G, Cuesta-Munoz A, Matschinsky F. Glucokinsae. In: Wiley Encyclopedia of molecular Medicine. Wiley and Sons, New York 2002; 1437-1441
• 35 Vaxillaire M, Rouard M, Yamagata K et al. Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).  Hum Mol Genet. 1997;  6 583-586
• 36 Awata T, Kurihara S, Inoue K et al. A novel missense mutation in the homeodomain of the hepatocyte nuclear factor-1alpha / maturity-onset diabetes of the young 3 in a Japanese early-onset type 2 diabetic patient and time-course of glucose-stimulated insulin secretion.  Diabetes Care. 1998;  21 1569-1571
• 37 Yamada S, Tomura H, Nishigori H et al. Identification of mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with early-onset NIDDM and functional analysis of the mutant proteins.  Diabetes. 1999;  48 645-648
• 38 Iafusco D, Stazi M A, Cotichini R et al. Early onset diabetes study group of the italian society of paediatric endocrinology and diabetology. Permanent diabetes mellitus in the first year of life.  Diabetologia. 2002;  45 798-804
• 39 Galan M, Vincent O, Roncero I et al. Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations on glucokinase activity and protein stability.  Biochem J. 2006;  393 389-396
• 40 Wang H, Antinozzi P A, Hagenfeldt K A et al. Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction.  EMBO J. 2000;  19 4257-4264
• 41 Slingerland A S. Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient.  Rev Endocr Metab Disord. 2006;  7 171-185