By David N. Leff

The legendary Willie Sutton took to robbing banks, he told his lawyers, "because that's where the money is." Molecular geneticists map the DNA of chromosomes because that's where the genes are that cause human diseases.

Until recent years, the trail they followed was posted, "One gene, one disorder." That spoor led to discovery of the genes for such rare monogenic maladies as muscular dystrophy, Gaucher's disease, Huntington's chorea - the list is long. But their gene hunt fell by the wayside when it came to the complex, polygenic disorders - notably asthma, hypertension, obesity, schizophrenia and diabetes.

These are the far-from-rare diseases that curse the Western industrialized world with out-of-control public health burdens. Take diabetes mellitus, for example. It comes in two persuasions - Type I and Type II. Diabetes is the seventh leading killer in the U.S., where its care costs $98 million a year. It's the No. 1 cause of limb amputations and kidney failure; a leading cause of heart disease, stroke, nerve damage and blindness.

Type I (also known as juvenile or early-onset diabetes) is an autoimmune disease, in which the victim's immune system rains friendly fire on the insulin-secreting islet cells that keep the body's glucose on an even keel. Type I afflicts only one in 20 people with diabetes mellitus.

The other 95 percent suffer from Type II - non-insulin-dependent diabetes mellitus (NIDDM). They number an estimated 135 million people worldwide, including more than 15 million Americans. That's almost 6 percent of the U.S. population, but thrice that many of them are over 65 years of age.

Type I diabetes strikes children and adolescents; Type II, people in their 40s and 50s. Type II diabetics either can't produce enough insulin or can't use it effectively to control glucose balance. Therefore, their sugar piles up in the blood, where it slowly, inexorably, ravages the cardiovascular system, kidneys, eyes and nerves.

Positional Cloning Corners First Type II Gene

Academic and pharmaceutical laboratories throughout the Western world have long been in hot pursuit of the multiple genes - number and location unknown - that express the proteins that perpetrate type II diabetes. Now at last, the October 2000 issue of Nature Genetics, released today, Sept. 27, 2000, can report: "Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus." Its co-senior authors, at the University of Chicago, are molecular biologist Graeme Bell, of the Howard Hughes Medical Institute, and human geneticist Nancy Cox.

Five years ago, Bell led the international team that tracked the first-ever Type II diabetogenic gene to somewhere (but where?) in the dense 5-million-base-pair DNA jungle of human chromosome 2's long arm. To begin with, by linkage analysis, they collected 330 pairs of adult Mexican-American siblings in Texas who had type 2 diabetes.

Mexican-Americans have twice or thrice the prevalence of Type II than does the U.S. population as a whole. But the even more grossly obese Pima Indians of the American Southwest run to 60 percent or 70 percent. Interestingly, the team's Mexican-American blood samples contained a 31 percent admixture of Amerindian blood. (See BioWorld Today, May 31, 1996, p. 1.)

Bell and his multi-national co-authors gave that unknown diabetes susceptibility gene the tentative designation of NIDDM1 - standing for "non-insulin-dependent diabetes mellitus." In that set of families, the affected sibs showed more sharing of chromosomal alleles - the strongest evidence of linkage - than would arise from chance alone.

"Since 1996," Cox told BioWorld Today, "we've been doing the positional cloning of that gene in the DNA of the same 330 affected Mexican-American sib pairs - going from linkage to actual gene sequence. A lot of DNA sequencing work and a lot of genetic analysis were the two primary things we've done for the past five years.

"The key results of our positional cloning studies," Cox observed, "was the identification of calpain-10 (CA-10) as the gene we originally called NIDDM1 - which gave rise to the evidence of gene linkage in the first place. We don't understand yet," she added, "what calpains do, so all we can say is that there's genetic variation in CA-10 that both increases and decreases the risk of developing diabetes."

How CA-10 might influence glucose metabolism, Cox ventured, "is information that would come at this point primarily from the study on Pima Indians, because they found that some of the genetic variation that we saw in the CA-10 gene is associated with insulin resistance and with reduced messenger RNA levels in skeletal muscle. That's consistent with our hypothesis that the variation we identified - which was all from noncoding sequences - would exert its effects by changing the expression of the amount of protein produced, rather than the particular type of protein.

"CA-10 is a ubiquitous processing protease that presumably clips lots of other proteins at a single location, usually to either activate or inactivate them. So what we're trying to do now is find out what some of the substrates are for the CA10 protease. Then we might have a better idea of how changes in the amount of CA10 in different tissues might affect susceptibility to diabetes."

Cox and her associates view their CA-10 protease as "a potentially druggable target. We've got a lot of corroborative data now suggesting that genetic variation of CA-10 affects susceptibility to disease. That allows us to put forward the hypothesis that CA-10 is indeed implicated in glucose homeostasis, and throws open a whole new avenue for drug-design research.

"Of course, everybody's interested in knowing whether this new pathway could lead to more effective, more specific, therapies for people with diabetes."

Flabby Abs Lead To Obesity, Diabetes

"There's a number of drugs now that are given to treat various disorders," she pointed out, "but have as a side effect, the development of Type II diabetes. The one that's gotten the most attention lately is where the HAART protease inhibitors given to AIDS patients, a substantial minority of whom develop lipodystrophy, with a redistribution of fat from trunkal areas to the abdominal area. They get abdominal fat. And that leads to insulin resistance, and a sizable minority of those patients go on to type II.

"But that would seem like a good clue to a different take on pharmacogenetics, maybe, pathways we should be trying to understand."

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