Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.-猫眼课题宝

DOI：

发表时间：

2005-05

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JOP : Journal of the pancreas

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其他

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作者：

A. Domínguez-López;Á. Miliar-García;Y. Segura-Kato;L. Riba;Riba Esparza-López;S. Ramírez-Jiménez;M. Rodríguez-Torres;S. Canizales-Quinteros;Siraam Cabrera-Vásquez;Verónica Fragoso-Ontiveros;C. Aguilar-Salinas;N. Altamirano-Bustamante;R. Calzada-León;C. Robles-Valdés;L. E. Bravo-Ríos;M. Tusié-Luna

研究背景青年成熟型糖尿病(MODY)是一种单基因糖尿病，具有常染色体显性遗传、发病年龄早、胰岛素分泌缺陷等特点。某些MODY基因序列变异可能与2型糖尿病的多基因形式有关。目的探讨MODY基因在23个墨西哥早发性糖尿病家系中的致病作用，其中包括5个具有常染色体显性遗传的家系。患者对23个早发性2型糖尿病患者无血缘关系的墨西哥家庭进行了研究，这些家庭此前曾被筛查过葡萄糖激酶突变。设计：应用聚合酶链式反应-单链构象多态性分析和自动测序技术筛选MODY基因的序列变异。我们在体外对HNF-1αP379H重组蛋白在HeLa和RINm5fβ细胞系中进行了功能分析。主要观察指标MODY基因突变筛查和P379H突变蛋白反式激活试验。结果在所研究的家系中均未检测到HNF-4α、IPF-1、NEUROD1或HNF-1β基因突变。在一个MODY家系中发现了HNF-1α基因的一个新突变(P379H)。RINm5f和HeLa细胞转染实验表明，突变蛋白对人胰岛素启动子的反式激活活性降低。结论在包括5个MODY家系在内的早发性糖尿病家系队列中，所有已知的MODY基因都被筛查出异常。我们发现了一个新的HNF-1αMODY突变(P379H)，并证明它降低了突变蛋白在人类胰岛素启动子上的反式激活潜力。在这个队列中没有发现其他突变，这表明MODY基因的异常通常不是早发性糖尿病的常见原因，这包括墨西哥的MODY家族。

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.

Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.

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