Back to Search
Start Over
Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 8/25/2009, Vol. 106 Issue 34, p14460-14465. 6p. 2 Charts, 3 Graphs. - 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 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 106
- Issue :
- 34
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 44758946
- Full Text :
- https://doi.org/10.1073/pnas.0906474106