Mutations at the BLK Locus Linked to Maturity Onset Diabetes of the Young and ß-Cell Dysfunction

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 34; pp. 14460 - 14465
• Main Authors: Borowiec, Maciej, Liew, Chong W., Thompson, Ryan, Boonyasrisawat, Watip, Hu, Jiang, Mlynarski, Wojciech M., Khattabi, Ilham El, Kim, Sung-Hoon, Marselli, Lorella, Rich, Stephen S., Krolewski, Andrzej S., Bonner-Weir, Susan, Sharma, Arun, Sale, Michele, Mychaleckyj, Josyf C., Kulkarni, Rohit N., Doria, Alessandro, Kahn, C. Ronald
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 25.08.2009
• Subjects: Cell lines; Diabetes; Genes; Genetic loci; Genetic mutation; Insulin; Insulin secretion; Secretion; Transcription factors; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906474106

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 ß-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 ß-cell function, the deficit of which may lead to the development of diabetes.