Joslin Researchers Shed Light on Genetic Defects that Cause Diabetes

Findings may lead to improved treatments for the disease

BOSTON — November 25, 2002 — 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.

New findings by Joslin Diabetes Center researchers headed by Steven E. Shoelson, M.D., Ph.D., head of the Cellular and Molecular Physiology section at Joslin and the Helen and Morton Adler Chair in Structural Biology, visualize the protein that is mutated in most individuals having a form of diabetes called Maturity Onset Diabetes of the Young (MODY). “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,” Shoelson said.

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.

Other Joslin researchers involved in the study included Young-In Chi, J. Daniel Frantz, Byung-Chul Oh, Lone Hansen, Sirano Dhe-Paganon.