title: Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY).
abstract: Maturity-onset diabetes of the young is a genetically heterogeneous autosomal dominant form of diabetes mellitus, characterized by an early age at onset and a primary defect in beta-cell function. Forty families with a clinical presentation suggestive of MODY were screened for the most common MODY subtypes caused by mutations in the genes encoding glucokinase (GCK, MODY2) and hepatocyte nuclear 1-alpha (HNF1A/TCF1, MODY3). Overall, 14 mutations were found (35%) giving a relative frequency of 22.5% and 12.5% for MODY2 and MODY3, respectively. Five of the nine GCK mutations identified were novel and included two deletions, two nonsense, and one splice site mutation. The GCK splice donor mutation was shown to result in an aberrant transcript owing to the recruitment of a cryptic splice site. The translated protein is predicted to contain an in frame insertion of nine amino acids. Among the five HNF1A mutations identified, three were novel comprising one missense mutation, one deletion, and one insertion. In addition, several novel polymorphisms within GCK were identified and their allele frequencies estimated. Knowledge of the genetic cause of MODY has significant impact on therapeutic decision making and may help to identify family members at risk for diabetes.
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Technische Universität Dresden, Dresden, Germany.
authors.forename: Dalia
authors.initials: D
authors.lastname: Toaima
authors.forename: Andrea
authors.initials: A
authors.lastname: Näke
authors.forename: Jutta
authors.initials: J
authors.lastname: Wendenburg
authors.forename: Kirsten
authors.initials: K
authors.lastname: Praedicow
authors.forename: Julia
authors.initials: J
authors.lastname: Rohayem
authors.forename: Kerstin
authors.initials: K
authors.lastname: Engel
authors.forename: Angela
authors.initials: A
authors.lastname: Galler
authors.forename: Manfred
authors.initials: M
authors.lastname: Gahr
authors.forename: Min Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005858:Germany / Q000208:ethnology; D005941:Glucokinase / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D005941:Glucokinase