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Defective Growth Gene in Rare Dwarfism Disorder Stunts Cancer and Diabetes

A long-term study shows that people with Laron syndrome, a genetically based form of dwarfism, almost never succumb to cancer or diabetes ByNina Bai For the past 22 years Jaime Guevara-Aguirre has served as the de facto physician for a truly unique community in Ecuador. His patients stand on average 1.2 meters tall, a result of a rare genetic disorder known as Laron syndrome. Of the approximately 300 people in the world known to have the condition, a third reside in the remote mountainside villages of southern Ecuador. Another remarkable fact about Guevara-Aguirres patients: virtually none of them suffer from cancer or diabetes. The same genetic mutationan error in the growth hormone receptor (GHR) genethat causes unusually small stature in Laron syndrome also confers seeming immunity from two of the most common diseases that plague mankind. Since 1988 no cases of diabetes and only one case of nonlethal cancer have been diagnosed in 99 Laron's subjects followed by Guevara-Aguirre. In comparison, fellow villagers without the GHR mutation had a diabetes diagnosis rate of 5 percent and a cancer diagnosis rate of 17 percent over the study period. GHR-deficient individuals are insensitive to growth hormone and also have abnormally low levels of insulinlike growth factor 1 (IGF1), a hormone that promotes cell proliferation and inhibits programmed cell death. More than two decades of clinical observations by Guevara-Aguirre's team are now supported by molecular studies linking low levels of IGF1 to cellular protection against cancer and other age-related diseases. "If we can establish that IGF1 is a risk factor for cancer, then you could imagine that doctors could prescribe IGF1lowering drugs as we are now doing for cholesterol with statins," says Valter Longo of the University of Southern California's Programs in Biomedical and Biological Sciences, who collaborated with Guevara-Aguirre on a study of the Ecuadorian community published February 16 in Science Translational Medicine. To investigate the cellular responses to IGF1, researchers bathed isolated human cells in blood serum taken from Laron subjects and from relatives without the mutation. When exposed to a toxin, cells bathed in Laron serum suffered fewer DNA breaks, suggesting that the lack of IGF1 protects against oxidative DNA damage. The protection disappeared when IGF1 was artificially added to the Laron serum. "I can say that we both came to the same conclusion from different routes Valter from the basic, and I from the clinical sciences"says Guevara-Aguirre, who is the medical director at the Institute of Endocrinology, 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 mutation have low cancer rates, increased insulin sensitivity that protects against diabetes, and extended life span. But it was impossible to study IGF1 in humans in the same way due to the extreme rarity of the naturally occurring GHR mutation. Meanwhile, Guevara-Aguirre had been studying the distorted body composition in the Laron subjects, but was struck by their unusual resistance to common diseases. "In 1988 I noticed that these patients had no diabetes despite being obese. In 1994 I also noticed they had no cancer. A few years later we documented they were insulin sensitive. These facts were fascinating to me," he says. When Longo heard about Guevara-Aguirre's work and his close relationship with such a large population of Laron's subjects, he realized that it could be the "perfect natural experiment." The study represents the first time that the GHR-deficiency mutation has been studied in a human population. Unlike dwarf mice, however, people with Laron syndrome do not seem to experience increased longevity. The effect on life span may have been obscured in this study by the unusually high number of accidents and alcohol-related deaths seen 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 have important implications for the general population. It is already known that IGF1 can be modulated by dietspecifically, that protein restriction lowers IGF1 levels. "All the data is coming together now," says Luigi Fontana who studies nutrition and aging at Washington University in Saint Louis School of Medicine and was not involved in the study. "Put together all the pieces of the puzzle and you see that yes, IGF1 is an important determinant of cancer." According to Fontana, greater protein intake and higher IGF1 levels contribute to the increasing cancer incidence in recent generations; a similar trend is seen in immigrant populations that move from Eastern to Western diets. However, Longo cautions, "people shouldn't make up their own diets to try to extend their life. If you don't have a clear disclaimer, you will 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 disease and cognitive decline. He hopes to extend the current study but acknowledges that the lower prevalence of these conditions, compared with that of cancer and diabetes, make them more difficult to study in a population of limited size.

The Ballooning Brain: Defective Genes May Explain Uncontrolled Brain Growth in Autism
Autistic children's brains may grow too big, too soon. A new study links this unusual growth to abnormal gene activity that fails to prune unnecessary neural connections ByFerris Jabr As a baby grows inside the womb, its brain does not simply expand like a dehydrated sponge dropped in water. Early brain development is an elaborate procession. Every minute some 250,000 neurons bloom, squirming past one another like so many schoolchildren rushing to their seats at the sound of the bell. Each neuron grows a long root at one end and a crown of branches at the other, linking itself to fellow cells near and far. By the end of the second trimester, neurons in the baby's brain have formed trillions of connections, many of which will not survive into adulthoodthe least traveled paths will eventually wither. Sometimes, the developing brain blunders, resulting in "neuro-developmental disorders," such as autism. But exactly why or how early cellular mistakes cause autism has eluded medical science. Now, Eric Courchesne of the University of California, San Diego, thinks he has linked atypical gene activity to excessive growth in the autistic brain. With the new data, he has started to trace a cascade of genetic and cellular changes that he thinks define autism. Although intrigued by Courchesne's work, other researchers caution that explosive neural growth is not necessarily a defining feature of all autistic brains. Since 1998 Courchesne has been searching autistic brains for unusual structural features. His studies suggest that while in the womb, the autistic brain sprouts an excess of neurons and continues to balloon during the first five years of life, as all those extra neurons grow larger and form connections. Sometime after age four or five, Courchesne has also found, autistic brains actually start to lose neural connections, faster than typical brains. In a study published November 2011 in JAMA, The Journal of the American Medical Association, Courchesne reported that children with autism have 67 percent more neurons in their prefrontal cortex (PFC) than typical children. Located in the area of the brain just behind the eyes, the PFC is responsible for what psychologists call "executive functions"high-level thinking, such as planning ahead, inhibiting impulses and directing attention. In his 2011 study Courchesne sliced up brain tissue from six autistic children and seven typical children who had passed away and counted the number of cell bodies in the sections to estimate the total number of neurons in their PFCs. Now, Courchesne and his colleagues have analyzed DNA and RNA in 33 cubes of brain tissue from people who passed away, 15 of whom were autistic (nine children and six adults) and 18 who had typical brains (seven children and 11 adults). Looking at the order of DNA's building blocks reveals whether individual genes have mutations; measuring levels of RNA indicates how often those genes were translated into proteins. Such gene expression, Courchesne and his colleagues found, varied between autistic and typical brains. In brain tissue from both autistic

children and autistic adults, genes coding for proteins that identify and repair mistakes in DNA were expressed at unusually low levels. Additionally, all autistic brains demonstrated unusual activity levels for genes that determine when neurons grow and die and how newborn neurons migrate during early development. Some genes involved in immune responses, cell-to-cell communication and tissue repair, however, were expressed at unusual levels in adult autistic brains, but not in autistic children's brains. The results appear in the March 22 issue of PLoS Genetics. By combining his new findings with his earlier discoveries, Courchesne has started to construct a kind of timeline of autism in the brain. Perhaps, as the brain of a future autistic child develops in the womb, something an inherited mutation or an environmental factor like a virus, toxin or hormone muffles the expression of genes coding for proteins that usually fix mistakes in sequences of DNA. Errors accumulate. The genetic systems controlling the growth of new neurons go haywire, and brain cells divide much more frequently than usual, accounting for the excess neurons found in the PFC of autistic children. Between birth and age five, the extra neurons in the autistic brain grow physically larger and form more connections than in a typical child's brain. Unused connections are not pruned away as they should be. Later, in adolescence and adulthood, the immune system reacts against the brain's overzealous growth, which might explain the unusual levels of immune genes Courchesne found in his new study and why, in earlier work, he had discovered that when autistic children become teenagers, some brain regions actually start shrinking compared with typical brains. Not all researchers, however, accept that the patterns of brain growth Courchesne has discovered are relevant to everyone with autism. Nicholas Lange, a biostatistician in the psychiatry department at Harvard Medical School, says that Courchesne analyzed too few samples in his new study to generalize the results to the larger autistic community. Some researchers have surfaced evidence that around 15 percent of autistic children have smaller than usual heads, a condition known as microcephaly, which indicates an abnormally small brain. David Amaral of the University of California, Davis, has previously told reporters that in an unpublished neuroimaging study, he found that only about 11 of 114 autistic children had unusually large brains. Other researchers point out that, in his research with tissue samples from brain banks, Courchesne fails to compare the number of neurons in the cerebral cortex with other parts of the brainit remains unclear why only the PFC would explode in growth. But acquiring enough preserved tissue from brain banks to conduct meaningful studies is no easy task they are incredibly coveted resources, and Courchesne's new study relies on a respectable sample. Looking at gene expression in postmortem brain tissue offers insights into the biology of autism that neuroimaging studies and analysis of DNA and RNA in blood cannot provide because different cell types express different sets of genes. Courchesne's newest findings at least partially echo earlier research by Daniel Geschwind of the University of California, Los Angeles, who also linked autism to unusual activity of genes that control immune responses and how neurons organize themselves in the developing brain. Although Courchesne's concept of autistic brain development is far from flawless or complete, it remains one of the most cohesive theories offered so far one that suggests the possibility of treatment as well. If scientists definitively link autism to a characteristic sequence of changes in gene expression and unusual neural growth, then it becomes possible to target and reverse any one of the thousands of steps in that sequence.

"Each individual autistic person likely has their own specific profile of dysregulated [sic] genes," Courchesne says, "which means that autism is a very complicated problem. But it's now knowable. We are getting at core knowledge. If we confirm that the starting point is gene activity, we can do something about it, because gene activity can be modified."

Disease That Stunts Infants' Growth Traced to Same Gene That Makes Kids Grow Too Fast
May 27, 2012 UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants' growth. The twist? The mutation occurs on the same gene that causes Beckwith-Wiedemann syndrome, which makes cells grow too fast, leading to very large children. Published in the May 27 edition of Nature Genetics, the UCLA findings could lead to new ways of blocking the rapid cell division that allows tumors to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to accurately identify. The discovery holds special significance for principal investigator Dr. Eric Vilain, a professor of human genetics, pediatrics and urology at the David Geffen School of Medicine at UCLA. Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, both children shared a mysterious malady marked by minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals. "I never found a reason to explain these patients' unusual set of symptoms," explained Vilain, who is also director of the UCLA Institute for Society and Genetics. "I've been searching for the cause of their disease since 1993." When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His mentor, then UCLA geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analyzed the patients' DNA for mutations in suspect genes, but uncovered nothing. Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism, and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the condition's symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies. Over the next decade, about 20 cases were reported around the world. But the cause of IMAGe syndrome remained a mystery. Help arrived unexpectedly last year when Vilain received an email from Argentinian physician Dr. Ignacio Bergada, who had unearthed the 1999 journal article. He told Vilain about a large family he was treating in which eight members suffered the same symptoms described in the study. All of the family members agreed to send their DNA samples to UCLA for study. Vilain realized that he had stumbled across the scientific equivalent of winning the lottery. He assembled a team of UCLA researchers to partner with Bergada and London endocrinologist Dr. John Achermann. "At last we had enough samples to help us zero in on the gene responsible for the syndrome," Vilain said. "Sequencing technology had also advanced in sophistication over the past two decades, allowing us to quickly analyze the entire family's DNA samples." Vilain's team performed a linkage study, which identifies disease-related genetic markers passed down from one generation to another. The results steered Vilain to a huge swath of Chromosome 11. The UCLA Center for Clinical Genomics performed next-generation sequencing, a powerful new technique that enabled the scientists to scour the enormous area in just two weeks and tease out a slender stretch that held the culprit mutation. The team also uncovered the same mutation in the original three cases described by Vilain in 1999.

A word of explanation: Located on 23 pairs of chromosomes, human genes hold the codes for making cellular proteins, the building blocks for our bodies. Most of the human diseases resulting from mutations in a single gene can be blamed on changes in a protein-coding sequence. By scanning the entire exome, or protein-coding factory of the genome, clinical geneticists can interpret every gene variant to track down the mutations that produce a patient's disease and rapidly reach a clear-cut diagnosis. "We discovered a mutation in a tiny sliver of the chromosome that appeared in every family member affected by IMAGe syndrome," said Vilain. "This was a big step forward. Now we can use gene sequencing as a tool to screen for the disease and diagnose children early enough for them to benefit from medical intervention. "We were a little surprised, because the mutation was located on a famous gene recognized for causing BeckwithWiedemann syndrome," he added. "The two diseases are polar opposites of each other." Children born with Beckwith-Wiedemann syndrome -- named for the two doctors who discovered it -- grow very large with big adrenal glands, elongated bones and oversized internal organs. Because their cells grow so fast, children with the disorder typically die of cancer at a young age. The disease affects one in 15,000 births. "Finding opposite functions in the same gene is a rare biological phenomenon" emphasized Vilain. "When the mutation appeared in the slim section we identified, the infant developed IMAGe syndrome. If the mutation fell anywhere else in the gene, the child was born with Beckwith-Wiedemann. That's really quite remarkable." IMAGe syndrome patients also tend to die young due to poor adrenal activity, which physicians treat with hormonereplacement therapy. The findings proved that Vilain and his colleagues had identified the correct mutation, bringing his 20-year odyssey to a successful end. "Our findings leave no doubt that this set of symptoms is a true syndrome and not just a figment of my imagination," said Vilain. "What makes this special for me is finally being able to unravel what caused the life-threatening disease in the two patients I saw nearly 20 years ago," he added. "As a clinical scientist, the reward for successful research is uncovering new clues that allow us to help patients feel better by improving their medical care." The IMAGe mutation's ability to miniaturize organisms and halt growth could offer intriguing clinical benefits, he noted. "Our next effort will focus on manipulating the mutation's strong influence on growth to shrink tumors in the adrenal glands and other internal organs," explained Vilain. Vilain's coauthors included first author Valerie Arboleda, Hane Lee, Alice Fleming, Abhik Banerjee, Emmanuele Delot, Imilce Rodriguez-Fernandez, Esteban Dell'Angelica, Stanley Nelson and Julian Martinez-Agosto, all of UCLA; Bruno Ferraz-de-Souza of University of San Paulo in Brazil; Bergada of Hospital de Ninos Ricardo Gutierrez, Argentina; and Achermann of University College London Institute of Child Health. The study was funded by the Doris Duke Charitable Foundation, Wellcome Trust and National Institute of Child Health and Human Development (grants RO1HD068 and 1F31HD068136).