Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal pattern of inheritance and a young age at onset, often before age 25. MODY is genetically heterogeneous, with 8 distinct MODY genes identified to date and more believed to exist. We resequenced 732 kb of genomic sequence at 8p23 in 6 MODY families unlinked to known MODY genes that showed evidence of linkage at that location. Of the 410 sequence differences that we identified, 5 had a frequency <1% in the general population and segregated with diabetes in 3 of the families, including the 2 showing the strongest support for linkage at this location. The 5 mutations were all placed within 100 kb corresponding to the BLK gene. One resulted in an Ala71Thr substitution; the other 4 were noncoding and determined decreased in vitro promoter activity in reporter gene experiments. We found that BLK-a nonreceptor tyrosine-kinase of the src family of proto-oncogenes-is expressed in beta-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1. These actions are greatly attenuated by the Ala71Thr mutation. These findings point to BLK as a previously unrecognized modulator of beta-cell function, the deficit of which may lead to the development of diabetes.
|Autori:||Borowiec M;Liew CW;Thompson R;Boonyasrisawat W;Hu J;Mlynarski WM;El Khattabi I;Kim SH;Marselli L;Rich SS;Krolewski AS;Bonner-Weir S;Sharma A;Sale M;Mychaleckyj JC;Kulkarni RN;Doria A|
|Titolo:||Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction.|
|Anno del prodotto:||2009|
|Digital Object Identifier (DOI):||10.1073/pnas.0906474106|
|Appare nelle tipologie:||1.1 Articolo in rivista|