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Mutations at the BLK locus linked to maturity onset diabetes of the young and [beta]-cell dysfunction
- Source :
- Proceedings of the National Academy of Sciences of the United States. August 25, 2009, Vol. 106 Issue 34, p14460, 6 p.
- Publication Year :
- 2009
-
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 [beta]-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 [beta]-cell function, the deficit of which may lead to the development of diabetes. beta cells | genetics | MODY | tyrosine kinase
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 106
- Issue :
- 34
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.208129776