Aarón Domínguez-López, Ángel Miliar-García1, Yayoi X Segura-Kato, Laura Riba, José Esparza-López, Salvador Ramírez-Jiménez, Maribel Rodríguez-Torres, Samuel Canizales-Quinteros, Siraam Cabrera-Vásquez, Verónica Fragoso-Ontiveros, Carlos A Aguilar-Salinas, Nelly Altamirano-Bustamante, Raúl Calzada-León, Carlos Robles-Valdés, Luz E Bravo-Ríos, Maria Teresa Tusié-Luna
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.
We assessed the contribution of MODY genes to the etiology of type 2 earlyonset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance.
Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied.
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 RINm5fbeta-cell lines
Main outcome measures
MODY gene mutation screening and P379H mutant protein transactivation assay.
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.
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 earlyonset diabetes and this includes MODY families in Mexico.