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Discovery will allow diagnosis even in
gestation; study is published in Nature Genetics
FCM helps identifyar gene that causes four rare diseases
CLAYTON LEVY
 UA study initiated by researcher Carlos Eduardo Steiner, from the Department of Medical Genetics at the Faculty of Medical Sciences at Unicamp, resulted in the identification of the gene that causes four rare diseases that affect the human skeleton. Two of them are lethal. The work is described in the article, “Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis”, which has just been published by the journal Nature Genetics, one of the most respected scientific publications in the world.
Work involved a total of 25 scientists
According to Steiner, the discovery will make it possible to diagnose diseases during pregnancy through fetal DNA tests. In addition to the Unicamp researcher, another Brazilian, doctor Chong Ae Kim, from the University of São Paulo (USP), participated in the work, which includes a total of 25 scientists, including North American doctor Déborah Krakow, who works in the International Service of Skeletal Dysplasia Registry, a global center based in Los Angeles.
The identified gene is located on chromosome pair 3, out of a total of 23 pairs that make up the genetic map of the human body. Research has revealed that mutations in its structure cause spondylocarpothartic synostosis, a disease characterized by the fusion of the bones of the spine, hands and feet. As a result, growth becomes compromised and the lungs may be compressed, causing breathing problems. It is a disease with autosomal recessive inheritance, that is, people with just one copy of the gene can transmit it to other generations but do not develop the disease. The disease itself only occurs in individuals with two altered copies of the gene. The medical literature records less than 40 cases in the world, described until 2004, and Steiner raises doubts regarding the diagnosis of some reports. The discovery of the gene that causes this syndrome can help resolve these doubts, as it allows for an accurate diagnostic examination through DNA testing.
 The research also revealed that the same gene, when altered, causes three other different diseases, all affecting the skeleton. One of them is Larsen syndrome, which is characterized by recurrent joint dislocations. The other two are type I and type III atelosteogenesis, which cause bone malformations. Both are lethal, causing death during pregnancy or shortly after birth. Unlike spondylocarpotassial synostosis, these other three conditions have autosomal dominant inheritance, that is, one altered copy of the gene is enough to determine its onset. Another consequence of this research was the discovery that the two forms of atelosteogenesis, previously considered distinct entities, are caused by mutations in the same gene and may, in reality, represent variations of the same disease and not two different diseases.
 Research has indicated that the difference in the determination of each disease is related to the type of mutation found in the gene. According to Steiner, spondylocarpotassium synostosis is determined by a “stop” type change, which abruptly interrupts gene reading. “It’s like making a cake with an incomplete recipe”, compares the researcher. In the other three cases, the gene suffers “missense” mutations. In this case, instead of a sudden interruption, the genetic change causes parts of the gene to be read incorrectly. “It's as if the cake recipe indicates a quantity of a certain ingredient, but instead of that measurement, completely wrong measurements are used,” he explains.
In the three cases of diseases caused by missense modifications, the genetic alteration arises from a phenomenon called new mutation. “This is when the gene changes in the child being generated, without being altered in the parents, becoming the first case in that family”, explains Steiner. This type of mutation, according to him, can occur due to internal factors related to the person's chromosomal map, or external factors, such as viruses or radiation.
Steiner classifies the identification of the gene as an important advance in medicine. “It’s one more piece that fits into the puzzle of human genetics,” he says. According to him, despite the progress made by the Genome Project, there are still many gaps to be filled. To facilitate understanding, Steiner compares the human being's 46 chromosomes with books in which the recipes that determine the body's characteristics are written. The recipes are the genes. “We already know the books, but we still haven’t found all the recipes and we don’t even know exactly how many of them work”
Family provided first clues
The discovery of the gene that causes the four bone diseases was only possible after the doctor and researcher from the Department of Medical Genetics at FCM at Unicamp, Carlos Eduardo Steiner, began to study the case of a family from the rural area of the municipality of Socorro, in the region from Campinas. Of the ten siblings that make up the group, five have spondylocarpothartic synostosis. Although benign, the disease causes the bones of the spine, hands and feet to fuse, compromising growth and causing respiratory problems.
Steiner's attention was drawn after clinical examinations revealed that the five people with the disease had a change in the arteries at the back of the eye. Based on this fact, the researcher wrote a first article raising the hypothesis that ocular changes could be related to spondylocarpotarsal synostosis. The work was published in 2000 in the American Journal of Medical Genetics. Steiner's discovery was not confirmed by other researchers, but his study paved the way for research that would eventually identify the gene that caused the disease.
According to the doctor, the article caught the attention of the editor of the American Journal of Medical Genetics, John Optiz, who suggested that Steiner continue the work together with the American doctor and researcher Deborah Krakow, one of the most respected scientists at the International Service Registry of Skeletal Dysplasias, a global center based in Los Angeles. “She became interested in the case and asked me to send samples of the family’s DNA,” she says. To achieve this, it was necessary to establish a collaborative study between Unicamp and Cedars-Sinai Hospital in Los Angeles, approved by the FCM Ethics and Research Committee. From then on, the study gained momentum and began to involve other researchers from Deborah's team.
The research continued until mid-2003, when Steiner received an email from Deborah finally announcing the address of the gene causing the disease: chromosome 3, short arm, band 1.4. This discovery resulted in a new article, published in April 2004 in the prestigious Journal of Medical Genetics, based in England.
The location of the chromosome represented an important advance, but the gene itself still needed to be identified. In practice, according to Steiner, it was like looking for a specific cake recipe in a 46-volume library. “The location of chromosome 3 meant that we had found the book where the recipe was, but we still had to locate the exact page where it was written,” he explains. There was no need to wait long. The gene was finally identified in a short time, which resulted in the article also published in April by Nature Genetics, one of the most respected scientific publications in the world.
In addition to the efforts of the scientists involved in the work, Steiner highlights the role played by the Brazilian family that originated the studies. “It was fundamental participation,” he says. At 35 years old, the doctor has already published 16 scientific articles in various specialized publications. Born in Curitiba, Steiner completed his undergraduate degree at the Federal University of Paraná. In 1993 he joined Unicamp, where he completed his medical residency and completed his master's and doctorate. He currently works as a collaborating researcher at the FCM Department of Medical Genetics, where he carries out research and patient care, in addition to activities as an undergraduate and postgraduate professor.
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