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Title: Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction
Authors: 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
Harvard Medical School
Medical University of Lodz
University of Virginia
Mahidol University
Joslin Diabetes Center
Keywords: Multidisciplinary
Issue Date: 25-Aug-2009
Citation: Proceedings of the National Academy of Sciences of the United States of America. Vol.106, No.34 (2009), 14460-14465
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.
ISSN: 10916490
Appears in Collections:Scopus 2006-2010

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