Mutations at the BLK Locus Linked to Maturity Onset Diabetes of the Young and ß-Cell Dysfunction
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 gen...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 34; pp. 14460 - 14465 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
National Academy of Sciences
25.08.2009
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0906474106 |