31 Borowiec, M. Liew, C. W. Thompson, R. Boonyasrisawat, W. Hu, J. Mlynarski, W. M. El Khattabi, I. Kim, S. H. Marselli, L. Rich, S. S. Krolewski, A. S. Bonner-Weir, S. Sharma, A. Sale, M. Mychaleckyj, J. C. Kulkarni, R. N. Doria, A. 2009 Proc Natl Acad Sci U S A Aug 10 1091-6490 (Electronic) 19667185 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. Journal article http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19667185