JOP. J Pancreas (Online) 2005; 6(3):238-245. JOP. Journal of the Pancreas – http://www.joplink.net – Vol. 6, No. 3 – May 2005. [ISSN 1590-8577] 238 ORIGINAL ARTICLE Mutations in MODY Genes Are not Common Cause of Early-Onset Type 2 Diabetes in Mexican Families Aarón Domínguez-López 1 , Ángel Miliar-García 1,2 , Yayoi X Segura-Kato 1 , Laura Riba 1 , José Esparza-López 1 , Salvador Ramírez-Jiménez 1 , Maribel Rodríguez-Torres 1 , Samuel Canizales-Quinteros 1 , Siraam Cabrera-Vásquez 1 , Verónica Fragoso-Ontiveros 1 , Carlos A Aguilar-Salinas 3 , Nelly Altamirano-Bustamante 4 , Raúl Calzada-León 4 , Carlos Robles-Valdés 4 , Luz E Bravo-Ríos 5 , Maria Teresa Tusié-Luna 1 1 Molecular Biology and Genomic Medicine Unit, National Institute for Medical Sciences and Nutrition 'Salvador Zubirán' and Biomedical Research Institute at National Autonomous University of Mexico; 2 Postgraduate Studies and Research Section, School of Medicine, National Polytechnic Institute; 3 Endocrinology Department, National Institute for Medical Sciences and Nutrition 'Salvador Zubirán'; 4 Pediatric Endocrinology Department, National Institute of Pediatrics; 5 Pediatric Endocrinology Department, General Hospital Medical Center 'La Raza'. Mexico City, Mexico ABSTRACT Context 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. Objetive 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. Patients Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied. Design 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. Main outcome measures 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