Maciej BorowiecChong W. LiewRyan ThompsonWatip BoonyasrisawatJiang HuWojciech M. MlynarskiIlham El KhattabiSung Hoon KimLorella MarselliStephen S. RichAndrzej S. KrolewskiSusan Bonner-WeirArun SharmaMichele SaleJosyf C. MychaleckyjRohit N. KulkarniAlessandro DoriaHarvard Medical SchoolMedical University of LodzUniversity of VirginiaMahidol UniversityJoslin Diabetes Center2018-09-132018-09-132009-08-25Proceedings of the National Academy of Sciences of the United States of America. Vol.106, No.34 (2009), 14460-1446510916490002784242-s2.0-70149104834https://repository.li.mahidol.ac.th/handle/20.500.14594/28386Maturity-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 β-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 β-cell function, the deficit of which may lead to the development of diabetes.Mahidol UniversityMultidisciplinaryArticleSCOPUS10.1073/pnas.0906474106