posted 12/06/02
Researchers visualize the protein that is mutated in most
individuals having a form of diabetes called Maturity Onset Diabetes of the
Young (MODY).
For years scientists have sought to identify the genetic basis
for 'typical' type 2 diabetes, but this has proven to be incredibly difficult.
Along the way, however, scientists have discovered pieces of the puzzle -- the
genes that are mutated in more specialized forms of diabetes. These are new
findings by Joslin Diabetes Center researchers headed by Steven E. Shoelson,
M.D., Ph.D
Shoelson said, "These findings, reported in the
November issue of the journal Molecular Cell, provide a clear picture of why
mutations cause diabetes and potential avenues for improved treatments for the
disease,".
Among the factors that distinguish MODY from
typical type 2 diabetes are its inheritance pattern; it is passed on directly
from one generation to the next, and clinical onset that usually occurs before
age 25. "Of the six MODY genes identified over the past few years, one of the
genes, MODY3, is by far the most common. In fact the MODY3 mutations in a gene
called Hnf-1a are the most common of all genetic (monogenic) causes of
diabetes," Dr. Shoelson said.
To understand the molecular function of a
mutational hotspot, the scientists crystallized the protein bound to DNA. They
used x-ray crystallography to determine the structure of the complex.
"We determined the three-dimensional structure of
a hotspot in Hnf-1a where diabetes mutations cluster," Shoelson said. "Many of
the mutations disturb binding of the protein to DNA, while others disrupt
interactions in the protein itself."
"The Hnf-1a protein reads DNA sequences such as
the insulin gene, and is therefore necessary for normal insulin production.
Patients with mutations in Hnf-1a produce less insulin, which causes their
diabetes," Shoelson said. For more information, visit Joslin's website at
www.joslin.org.
Source: Diabetes In Control Dot Com.
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