title: Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.
abstract: BACKGROUND
  Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes.
  
  
  OBJECTIVE
  We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance.
  
  
  METHODS
  Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied.
  
  
  METHODS
  We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines.
  
  
  METHODS
  MODY gene mutation screening and P379H mutant protein transactivation assay.
  
  
  RESULTS
  No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H) of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter.
  
  
  CONCLUSIONS
  All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H) and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.
authors.affiliation: National Institute for Medical Sciences and Nutrition Salvador Zubirán, Biomedical Research Institute, National Autonomous University of Mexico, Mexico City, Mexico.
authors.forename: Aarón
authors.initials: A
authors.lastname: Domínguez-López
authors.forename: Angel
authors.initials: A
authors.lastname: Miliar-García
authors.forename: Yayoi X
authors.initials: YX
authors.lastname: Segura-Kato
authors.forename: Laura
authors.initials: L
authors.lastname: Riba
authors.forename: Riba
authors.initials: R
authors.lastname: Esparza-López
authors.forename: Salvador
authors.initials: S
authors.lastname: Ramírez-Jiménez
authors.forename: Maribel
authors.initials: M
authors.lastname: Rodríguez-Torres
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
authors.forename: Siraam
authors.initials: S
authors.lastname: Cabrera-Vásquez
authors.forename: Verónica
authors.initials: V
authors.lastname: Fragoso-Ontiveros
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.forename: Nelly
authors.initials: N
authors.lastname: Altamirano-Bustamante
authors.forename: Raúl
authors.initials: R
authors.lastname: Calzada-León
authors.forename: Carlos
authors.initials: C
authors.lastname: Robles-Valdés
authors.forename: Luz E
authors.initials: LE
authors.lastname: Bravo-Ríos
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Tusié-Luna
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015153:Blotting, Western; D015331:Cohort Studies; D004247:DNA / Q000032:analysis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology* / Q000209:etiology / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005820:Genetic Testing; D005941:Glucokinase / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008800:Mexico; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015534:Trans-Activators / Q000235:genetics; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D005941:Glucokinase; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D018398:Homeodomain Proteins; D015534:Trans-Activators; C496592:HNF4A protein, human; C093970:NEUROD1 protein, human; C084010:pancreatic and duodenal homeobox 1 protein