Publication: Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction
Issued Date
2009-08-25
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ISSN
10916490
00278424
00278424
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2-s2.0-70149104834
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Mahidol University
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SCOPUS
Bibliographic Citation
Proceedings of the National Academy of Sciences of the United States of America. Vol.106, No.34 (2009), 14460-14465
Suggested Citation
Maciej Borowiec, Chong W. Liew, Ryan Thompson, Watip Boonyasrisawat, Jiang Hu, Wojciech M. Mlynarski, Ilham El Khattabi, Sung Hoon Kim, Lorella Marselli, Stephen S. Rich, Andrzej S. Krolewski, Susan Bonner-Weir, Arun Sharma, Michele Sale, Josyf C. Mychaleckyj, Rohit N. Kulkarni, Alessandro Doria Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America. Vol.106, No.34 (2009), 14460-14465. doi:10.1073/pnas.0906474106 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/28386
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Title
Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction
Abstract
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 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.