One of the best aspects of researching a topic is serendipitously stumbling on news stories that would otherwise escape my attention. So imagine my pleasure when I happened across this short piece in the February 18 issue of Science Magazine. It describes Laron Syndrome, a disease that results in dwarfism, obesity and an increased risk of convulsive disorders, but also results in a dramatically reduced risk for diabetes and cancer. Jaime Guevara-Aguirre at the Institute of Endocrinology, Metabolism and Reproduction in Quito, Ecuador has been studying a cohort of patients in remote Ecuadoran villages for over 20 years (see below). Among the 152 living and dead Laron patients he has studied, not a single one had diabetes, despite having nearly twice the level of obesity as compared to their non-Laron relatives (5% of these people had diabetes). Even more startling, only one patient had a non-lethal case of cancer: an ovarian cancer treated with chemotherapy and in full remission at the time of death, compared to nearly 20% of the control (non-Laron relatives) cohort dying from cancer. Even more interesting, Guevara-Aguirre and his colleagues have an extraordinary molecular link bewteen this disease and cancer. [More after the break]
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| Guevara-Aguirre with several of his Laron syndrome subjects in 1988 (top) and in 2009 (bottom). CREDITS: JAIME GUEVARA-AGUIRRE ET AL., SCIENCE TRANSLATIONAL MEDICINE3, 70 (16 FEBRUARY 2011) |
It appears that all these clinical manifestations are a result of a single splicing mutation in a the Growth Hormone Receptor (GHR) gene that eliminates eight amino acids from the normal protein. In a mechanism that is not well understood, defective GHR results in cells that have fewer DNA strand breaks when exposed to hydrogen peroxide (a chemical used to induce these breaks). The significance of this is that fewer DNA breaks translate to less DNA damage and a reduced risk of mutations. Since mutations drive cancer, Laron patients are less likely than others to get cancer. Moreover, cells from Laron patients show increased levels of apoptosis in response to DNA damage. Evasion of apoptosis (programmed cell death) is one of the hallmarks of cancer; it allows highly mutated and/or damaged cells to continue to live. In contrast, these cells show a marked affinity to apoptose, thereby insuring that damaged cells will be thoroughly eliminated.
On the diabetes end of things, Aguirre and his colleagues show that insulin levels in Laron patients are very low compared to the control population, implying that their cells are highly sensitive to insulin levels resulting in a low (indeed, non-existant) level of diabetes. High insulin levels and insulin resistance are hallmarks of diabetes.
There is still much to understand. Why Laron patients have lower levels of DNA damage is still a mystery. Furthermore, why increased incidence of epilepsy and other convulsive disorders is a major cause of death (along with accidents, perhaps not surprisingly given their shorter stature) is poorly understood. Could GHR therapy be used to stave off cancer? Perhaps, but a more thorough understanding of its role in normal cells is needed before that can be tried.
For those interested, here is a link to Guevara-Aguire's paper in Science Translational Medicine. It may require a password; if so, please let me know and I can email the pdf file to you. Here is the PubMed Link if you'd like to read the abstract.
