Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.
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.
Domínguez-López
Aarón
A
National Institute for Medical Sciences and Nutrition Salvador Zubirán, Biomedical Research Institute, National Autonomous University of Mexico, Mexico City, Mexico.
Miliar-García
Angel
A
Segura-Kato
Yayoi X
YX
Riba
Laura
L
Esparza-López
Riba
R
Ramírez-Jiménez
Salvador
S
Rodríguez-Torres
Maribel
M
Canizales-Quinteros
Samuel
S
Cabrera-Vásquez
Siraam
S
Fragoso-Ontiveros
Verónica
V
Aguilar-Salinas
Carlos A
CA
Altamirano-Bustamante
Nelly
N
Calzada-León
Raúl
R
Robles-Valdés
Carlos
C
Bravo-Ríos
Luz E
LE
Tusié-Luna
Maria Teresa
MT
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
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