Surprising pair of diabetes genes debuts.

In 1861, an East Prussian couple emigrated to Detroit, bringing with them four sons, five daughters, and a secret that would last for more than a century.

The secret was the cause of a rare form of diabetes that afflicted four of the couple's nine offspring and at least 74 of more than 360 known descendants. That family secret is now out in the open.

In the Dec. 5 Nature, researchers who have painstakingly studied this lineage reveal the identity of a mutated gene responsible for the family's unfortunate excess of diabetes. The long-awaited success actually stems from the finding of another inherited diabetes gene in other families, which the same research group also describes in Nature.

Mutations in the two genes do not appear to be responsible for the more com- mon, noninherited forms of diabetes. Nonetheless, researchers believe that the genes and the proteins they encode, which regulate the activity of other genes, could offer insights into treating or preventing all types of diabetes.

"It's quite a nice piece of work. It draws attention to two proteins that clearly play a role in preventing diabetes," comments Simeon I. Taylor of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

In 1958, the diabetes-prone East Prussian descendants came to the attention of Stefan S. Fajans of the University of Michigan Medical Center in Ann Arbor. Fajans, who has gathered data on six generations of the lineage, found that family members suffered non-insulin-dependent diabetes mellitus (NIDDM), also called type II diabetes.

Yet the disease, which stems from an inability to control glucose concentra- tions in the blood, strikes unusually early in this family: It appears during adolescence or by the age of 25, rather than after age 40. This rare, inherited form of NIDDM is known as maturity-onset diabetes of the young, or MODY.

A research group headed by Graeme I. Bell of the Howard Hughes Medical Institute at the University of Chicago then joined with Fajans to take on the challenge of finding the responsible gene. In 1991, Bell and his colleagues localized the gene to a region on chromosome 20. That large span of DNA con- tained so many candidate genes that the search stalled, however.

Consequently, Bell's group began to study other families prone to early-onset NIDDM. In 1992, the researchers found that several of the families possess a mutant chromosome 12 gene that produces a defective enzyme involved in insulin's response to glucose (SN: 5/2/92, p. 300). From their studies of still other MODY families, the researchers concluded that the disease could result from a mutated gene somewhere on chromosome 7.

Bell's group has now identified mutations in a chromosome 7 gene called TCF1 as the cause of those families' diabetes. This discovery immediately made the researchers suspicious that a related gene, TCF14, which resides on chromosome 20, causes diabetes in the original MODY family studied by Fajans. Indeed, Bell's group quickly found mutations in TCF14 among family members with the disease.

These two diabetes genes encode transcription factors, proteins that bind to DNA and regulate the on-off activity of other genes. These particular proteins, called HNF-1alpha and HNF-4alpha, control genes in liver cells and in other tissues, including the pancreas, where the glucose-regulating hormone insulin is made.

Little is known about how the transcription factors might ultimately influence glucose concentrations, says Bell, noting that their involvement in diabetes comes as a surprise. "If you asked me to make a list of genes that could be responsible [for MODY], neither of these would be on my list," agrees Taylor.

HNF-4alpha controls the production of HNF-1alpha, so Bell suspects that muta- tions in each protein's gene trigger diabetes through a common pathway.

He and Taylor agree that the proteins, particularly HNF-4alpha, which is activated by an unknown molecule, are appealing targets for drug designers seeking to treat or prevent diabetes. The likely strategy, they say, will be to create or identify compounds able to influence the diabetes-preventing genes that the two proteins control.