Defective Growth Gene in Rare Dwarfism Disorder Stunts Cancer and Diabetes

StephenW

http://www.scientificamerican.com/article.cfm?id=defective-growth-gene-in-dwarfism&WT.mc_id=SA_CAT_BS_20110218
Defective Growth Gene in Rare Dwarfism Disorder Stunts Cancer and Diabetes                                

Along-term study shows that people with Laron syndrome, a geneticallybased form of dwarfism, almost never succumb to cancer or diabetes

By  Nina Bai   February 17, 2011   

HEIGHT MATTERS: Jaime Guevara-Aguirre poses with one of the study participants with Laron syndrome.   Image: Courtesy of Jaime Guevara-Aguirre                           

orthe past 22 years Jaime Guevara-Aguirre has served as the de factophysician for a truly unique community in Ecuador. His patients standon average 1.2 meters tall, a result of a rare genetic disorder knownas Laron syndrome.Of the approximately 300 people in the world known to have thecondition, a third reside in the remote mountainside villages ofsouthern Ecuador. Another remarkable fact about Guevara-Aguirre’spatients: virtually none of them suffer from cancer or diabetes.

The same genetic mutation—an error in the growth hormone receptor (GHR)gene—that causes unusually small stature in Laron syndrome also confersseeming immunity from two of the most common diseases that plaguemankind. Since 1988 no cases of diabetes and only one case of nonlethalcancer have been diagnosed in 99 Laron's subjects followed byGuevara-Aguirre. In comparison, fellow villagers without the GHRmutation had a diabetes diagnosis rate of 5 percent and a cancerdiagnosis rate of 17 percent over the study period.

GHR-deficient individuals are insensitive to growth hormoneand also have abnormally low levels of insulinlike growth factor 1(IGF1), a hormone that promotes cell proliferation and inhibitsprogrammed cell death. More than two decades of clinical observationsby Guevara-Aguirre's team are now supported by molecular studieslinking low levels of IGF1 to cellular protection against cancer andother age-related diseases.

"If we can establish that IGF1 is a risk factor for cancer, then youcould imagine that doctors could prescribe IGF1-lowering drugs as weare now doing for cholesterol with statins," says Valter Longoof the University of Southern California's Programs in Biomedical andBiological Sciences, who collaborated with Guevara-Aguirre on a studyof the Ecuadorian community published February 16 in Science Translational Medicine.

To investigate the cellular responses to IGF1, researchers bathedisolated human cells in blood serum taken from Laron subjects and fromrelatives without the mutation. When exposed to a toxin, cells bathedin Laron serum suffered fewer DNA breaks, suggesting that the lack ofIGF1 protects against oxidative DNA damage. The protection disappearedwhen IGF1 was artificially added to the Laron serum.

"I can say that we both came to the same conclusion from differentroutes—Valter from the basic, and I from the clinical sciences"—saysGuevara-Aguirre, who is the medical director at the Institute ofEndocrinology, Metabolism and Reproduction in Quito, Ecuador.

The two research teams began their collaboration in 2005. "I realized that nobody was working in humans that had a defect in GHR. We were working on all kinds of model systems," Longo says.

Previous work on model organisms had suggested the role of IGF1 in cancer prevention and aging. Dwarf mice with the same GHR mutationhave low cancer rates, increased insulin sensitivity that protectsagainst diabetes, and extended life span. But it was impossible tostudy IGF1 in humans in the same way due to the extreme rarity of thenaturally occurring GHR mutation.

Meanwhile, Guevara-Aguirre had been studying the distorted bodycomposition in the Laron subjects, but was struck by their unusualresistance to common diseases. "In 1988 I noticed that these patientshad no diabetes despite being obese. In 1994 I also noticed they had nocancer. A few years later we documented they were insulin sensitive.These facts were fascinating to me," he says. When Longo heard aboutGuevara-Aguirre's work and his close relationship with such a largepopulation of Laron's subjects, he realized that it could be the"perfect natural experiment."

The study represents the first time that the GHR-deficiencymutation has been studied in a human population. Unlike dwarf mice,however, people with Laron syndrome do not seem to experience increasedlongevity. The effect on life span may have been obscured in this studyby the unusually high number of accidents and alcohol-related deathsseen in the Laron subjects. "Being three-and-a-half feet tall,accidents just happen," Longo says.

Despite the extreme rarity of Laron syndrome, the study findings haveimportant implications for the general population. It is already knownthat IGF1 can be modulated by diet—specifically, that proteinrestriction lowers IGF1 levels.

"All the data is coming together now," says Luigi Fontanawho studies nutrition and aging at Washington University in Saint LouisSchool of Medicine and was not involved in the study. "Put together allthe pieces of the puzzle and you see that yes, IGF1 is an importantdeterminant of cancer." According to Fontana, greater protein intakeand higher IGF1 levels contribute to the increasing cancer incidence inrecent generations; a similar trend is seen in immigrant populationsthat move from Eastern to Western diets.

However, Longo cautions, "people shouldn't make up their own diets totry to extend their life. If you don't have a clear disclaimer, youwill be amazed at what people do."

Longo suspects the IGF1 pathway may be involved in the great majority of the diseases of aging, including osteoporosis, Alzheimer's diseaseand cognitive decline. He hopes to extend the current study butacknowledges that the lower prevalence of these conditions, comparedwith that of cancer and diabetes, make them more difficult to study ina population of limited size.