The enigma of the rare genetic mutation that protects against cancer and heart attacks

The study of Ecuadorian families with a rare disease known as Laron Syndrome has just shown that a genetic mutation protects them from cardiovascular diseases. Researchers believe that it is possible to search for a drug or a diet that mimics these beneficial effects in order to combat diseases associated with aging, such as cancer, in the general population.

In 1987, Ecuadorian endocrinologist Jaime Guevara-Aguirre began treating people with Laron Syndrome who lived in isolated towns in the provinces of Loja and El Oro, in the south of the country, near the border with Peru. The disease is characterized by a mutation in the growth hormone receptor gene that causes short stature. People with this condition do not exceed 1.5 meters (4 ft 10 in) in height. The cause is a mutation of a single biochemical letter — a G instead of an A — in the very long sequence of three billion letters that makes up the human genome. In these communities in Ecuador, endogamy is common, which has favored the spread of the syndrome. Even today, the inhabitants of these municipalities continue to have children without knowing if they will be born with Laron or not. In the family photos, affected parents are seen with their children of about 10 years of age, who are already taller than them.

In a teleconference from Quito, Guevara-Aguirre apologizes ahead of time in case communication is interrupted due to the blackouts that have been afflicting the country, which has been plunged into a spiral of violence and instability. “In 1987 it took two days to get to these towns in my father’s 4x4, and to get to some of them you had to walk two or three more hours. It was a very remote area, but the patients were fascinating,” recalls Guevara-Aguirre, of San Francisco de Quito University. Since then, he has diagnosed about 100 affected people, approximately a third of all known cases in the world.

After two decades of follow-up, the doctor observed an enigmatic pattern: there was hardly any cancer or diabetes in Laron’s carriers, while their apparently healthy relatives suffered from these ailments with the same frequency as the rest of Ecuadorians. The doctor posited that Laron’s mutation protects against diseases related to aging. The matter caught the attention of the biochemist Valter Longo, a researcher at the University of Southern California focused on the search for diets capable of stopping chronic diseases.

In 2011 they showed that people affected by Laron produced less IGF-1, a protein essential for childhood growth but which in adults also promotes uncontrolled cancer cell proliferation. In laboratory studies, mice with low levels of this protein live up to 40% longer, suffer fewer tumors, and appear smaller than normal.

In 2017, the pair of researchers published another study that pointed out that this mutation also protects against neurodegenerative ailments. Although very few affected people live beyond the age of 80, among those identified there were no cases of Alzheimer’s or dementia. While many of the relatives without the mutation suffered and died from diseases related to aging, those affected by the syndrome died mainly from accidents or alcoholism, which is very common in these Andean communities.

In their new work, the researchers posit that the Laron mutation also has a protective effect against cardiovascular diseases. They studied 21 men with the syndrome and 23 unaffected relatives. Carriers had lower glucose levels and blood pressure. Despite showing high levels of “bad” LDL cholesterol, they had much fewer arteriosclerosis plaques, according to the study, published in the specialized journal Med.

“This is the most important study of all,” Longo emphasizes. “Skeptics maintained that the most common cause of death in these people was heart problems, but we showed that this is not the case.” Many of the patients in the study are overweight or obese and lead a poor lifestyle, with high tobacco and alcohol consumption. “The worst thing is that we see that some of them feel that they can do whatever they want because they are protected, which is obviously not the case,” highlights the Italian-American biochemist, who has visited these villages in Ecuador “dozens of times.”

Longo highlights that diets that mimic fasting, which he himself has designed, lower IGF-1 levels in the circulation, the supposed cause of the beneficial effects observed both in animals and in people with Laron. Another of the authors of the work, John Kopchick, from the University of Ohio, has shown that several molecules that block the growth hormone receptor slow tumor progression in mice and in human breast cancer cells, and improve the effectiveness of conventional treatments. One of these molecules is Pegvisomant, an already approved drug manufactured by the multinational Pfizer to treat acromegaly, a hormonal imbalance that causes excessive growth of the face and extremities.

The Israeli doctor Zvi Laron discovered the syndrome in 1966 in highly consanguineous Jewish families from Yemen. In 2013, a genetic study pointed out that this mutation probably originates from Spanish and Portuguese Sephardic Jews who fled the Inquisition in the 15th century and founded small communities in Ecuador, Chile, and Brazil. There are 17 different mutations that cause Laron Syndrome, and one of them reached America, explains the scientist, professor emeritus at Tel Aviv University. In recent years, he has published several studies focused on how to replicate the cancer-protective effects he sees in these patients. The scientist believes that the results seen in Ecuador cannot be generalized. “In our cohort of 76 individuals, who were followed for many years, we have seen that the majority of older and obese patients develop insulin resistance and three men and eight women suffered from diabetes,” but only one of them has the same mutation as the Ecuadorians, he said. His next scientific goal is to calculate how many people actually suffer from this condition around the world. “There are probably more than 500, but in many countries they are never diagnosed,” he notes in a telephone conversation from Tel Aviv.

Laron Syndrome is recessive, which means that you have to inherit two mutated copies of the gene, one from the father and one from the mother, to suffer from it. It is possible for one person with the syndrome to have healthy children, and it is also possible for two people without the syndrome to carry the mutation and have children with Laron. “It’s a genetic lottery” that is amplified due to inbreeding, admits Guevara-Aguirre.

This doctor has shown that dwarfism can be treated by administering recombinant IGF-1 protein from an early age. Furthermore, since 1992, he has tried to establish a “massive” genetic diagnosis system that would allow these inhabitants to know if their partners are carriers of the mutation, but this has not yet been done. “It is an easy and cheap intervention, but it has not materialized due to the ignorance of the authorities,” he says.

Guevara-Aguirre's goal now is to determine whether carriers of the mutation live longer than their siblings and other relatives. “My feeling is yes, but it has to be proven. The problem is that this area is controlled by the narco-guerrilla,” he laments.

Alejandro Martín-Montalvo, a researcher at Spain’s National Research Council, collaborated with Longo and Guevara-Aguirre on their study on Laron and cancer in 2011. He considers that “this new work is an advance, as it shows that these people are not predisposed to cardiac failures as was believed until now. In addition, it opens up a possible new line of research on how to transfer these benefits to the general population.”

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