Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-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 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.
Borowiec
Maciej
M
Research Division, Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Liew
Chong W
CW
Thompson
Ryan
R
Boonyasrisawat
Watip
W
Hu
Jiang
J
Mlynarski
Wojciech M
WM
El Khattabi
Ilham
I
Kim
Sung-Hoon
SH
Marselli
Lorella
L
Rich
Stephen S
SS
Krolewski
Andrzej S
AS
Bonner-Weir
Susan
S
Sharma
Arun
A
Sale
Michele
M
Mychaleckyj
Josyf C
JC
Kulkarni
Rohit N
RN
Doria
Alessandro
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D011993:Recombinant Fusion Proteins; D008156:Luciferases; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases