TY - JOUR
T1 - Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families
AU - Domínguez-López, Aarón
AU - Miliar-García, Ángel
AU - Segura-Kato, Yayoi X.
AU - Riba, Laura
AU - Esparza-López, José
AU - Ramírez-Jiménez, Salvador
AU - Rodríguez-Torres, Maribel
AU - Canizales-Quinteros, Samuel
AU - Cabrera-Vásquez, Siraam
AU - Fragoso-Ontiveros, Verónica
AU - Aguilar-Salinas, Carlos A.
AU - Altamirano-Bustamante, Nelly
AU - Calzada-León, Raúl
AU - Robles-Valdés, Carlos
AU - Bravo-Ríos, Luz E.
AU - Tusié-Luna, Maria Teresa
PY - 2005/5
Y1 - 2005/5
N2 - 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. 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. 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 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.
AB - 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. 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. 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 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.
KW - Genetics
KW - Mexico
KW - Polymorphism, genetic
UR - http://www.scopus.com/inward/record.url?scp=27644491272&partnerID=8YFLogxK
M3 - Artículo
SN - 1590-8577
VL - 6
SP - 238
EP - 245
JO - Journal of the Pancreas
JF - Journal of the Pancreas
IS - 3
ER -