LONDON — The excitement over the discovery of leptin and its role in obesity in mice just a few years ago was quickly followed by disappointment that mutations in the genes for leptin and its receptor in obese humans were exceedingly rare. But, at long last, the search for other genes with a role in obesity in humans is beginning to reap rewards.

The latest discovery demonstrates to those who doubted it that obesity can be inherited as a single-gene disorder, and provides a new target for pharmaceutical companies hoping to develop drugs to control the Western world's "epidemic" of obesity.

Two groups report in the October issue of Nature Genetics that mutations in the gene for the melanocortin-4 receptor (MC4R) result in a truncated message, and obesity in those individuals who inherit the mutated gene.

Stephen O'Rahilly, of the university departments of medicine and clinical biochemistry at Addenbrooke's Hospital, in Cambridge, U.K., and colleagues describe their study in a letter titled "A frameshift mutation in MC4R associated with dominantly inherited human obesity." The second letter, titled "A frameshift mutation in human MC4R is associated with a dominant form of obesity," is from Philippe Froguel, of the Institut Pasteur de Lille, in France, and colleagues.

The melanocortin-4 receptor is found on cells in the hypothalamus. It is a seven-transmembrane G-protein that is activated by a molecule called alpha-MSH. Researchers began to focus their attention on the melanocortin-4 receptor for several reasons. First, its activity is directly linked to that of leptin. When leptin binds to the brain, it stimulates induction of alpha-MSH, which activates the melanocortin-4 receptor.

Second, the knockout mouse lacking this receptor is obese. Third, agouti yellow mice — which are naturally obese — produce the agouti protein, which is an antagonist of the melanocortin-4 receptor.

O'Rahilly and colleagues, and Froguel and colleagues, searched for mutations in the gene for the melanocortin-4 receptor among their cohorts of naturally obese patients. Froguel told BioWorld International: "In human genetics, it's not only important to have a good idea; probably the most important thing is to have a good collection of DNA. The key issue is to have access to patients with a good phenotype — those with a strong family history of obesity with onset at a young age and with characteristics that suggest that genetic rather than psychological factors are the cause of the condition."

After screening 43 people with a history of obesity from infancy, Froguel's group found one person with a mutation in the melanocortin-4 receptor gene. This mutation, which was heterozygous, comprised the insertion of four base pairs early in the coding sequence, resulting in a frameshift. The resulting protein was therefore truncated, lacking the sixth and seventh transmembrane domains.

This patient was a woman who at age 20, with a height of 163 centimeters, weighed 80 kilograms, giving a body mass index (BMI) of 30 kilograms per square meter. (People of normal weight have a BMI of 25 kilograms per square meter or under. Those with a BMI of 25 to 30 are classified as overweight, and those with a BMI of 30 or over are classed as obese.) By the age of 35, this woman was severely obese, with an estimated 65 percent of her weight due to fat (compared to 25 to 30 percent in a normal person). Her mother, sister, brother and a niece have a similar weight history.

Tests showed that the mutation was not present in controls of normal weight, and that the mutation was present in obese members of the patient's family but not in those of normal weight. Froguel and his colleagues write: "Our data indicate that a mutation in MC4R can cause a nonsyndromic form of obesity with a monogenic dominant form of inheritance in humans."

O'Rahilly and his group likewise screened 63 severely obese children. They found one child who was heterozygous for a mutation which, like that found by the French researchers, resulted in a frameshift. This, too, meant that the protein made by the mutated gene would be truncated, and lack part of the fifth and the sixth transmembrane domain.

The U.K. group writes: "As residues at the base of the fifth and sixth transmembrane domains are needed for G-protein binding and activation, this mutation is likely to result in a non-functional receptor."

The child with this mutation weighed 3.8 kilograms at birth, but began putting on excess weight from the age of four months. At four years, his weight was 32 kilograms with a height of 107 centimeters, giving him a BMI of 28 kilograms per square meter, which is very high for a child. The child's father is also obese, weighing 139 kilograms and with a BMI of 41 kilograms per square meter. He, too, was found to be heterozygous for the same mutation.

Although not yet published, Froguel's group has identified a further 10 missense mutations and currently is working on establishing whether these affect the functioning of the melanocortin-4 receptor, and whether they are found only among the obese members of affected families. O'Rahilly's group, likewise, has found another three families with mutations affecting this gene.

O'Rahilly told BioWorld International that, judging by discussions at the International Congress on Obesity, held recently in Paris, there are "many more families being worked up in which the melanocortin-4 receptor is mutated. This mutation seems to be much more common among obese people than those affecting leptin, the leptin receptor or alpha-MSH."

All of the molecules mentioned by O'Rahilly could form targets for drugs aimed at controlling obesity. "Clearly," he said, "when these molecules go wrong, obesity is the result, so if you can stimulate them, or whatever, you might be able to reverse the obesity." The melanocortin-4 receptor could provide the best target yet, he added, partly because it is more common and "even more important, because it seems that losing only 50 percent of the receptor is enough to make you obese, which suggests that some subtle changes in melanocortin-4 signaling might be enough to regulate appetite."

A further advantage, said Froguel, is that patients with this mutation are obese but otherwise normal — unlike some of the mutations in related molecules that are associated with delayed puberty, short stature and other endocrinological problems.

"It is a very pure form of obesity, which means it is probably more similar to the most common form of obesity," Froguel said. He believes that several pharmaceutical companies currently are working on patenting small molecules to target the melanocortin-4 receptor. *

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