As a service to reporters, the public, and the research community, the embargo time on Science paper #23, by De Sandre-Giovannoli et al. has changed to 2 pm US Eastern Time, Wednesday 16 April 2003 to coincide with the release of another progeria research paper.
A France-based research team has discovered the gene responsible for Hutchinson-Gilford Progeria, a disease whose young victims age five to ten times faster than normal.
Pinpointing the gene is a critical starting point for developing therapies for the disorder and programs to screen individuals for the defective gene, according to the researchers. Their findings appear in the journal Science, published by the American Association for the Advancement of Science.
"Without knowing what caused this type of progeria, we had little idea how we might someday treat it. Identifying the gene responsible for the disease is a critical step toward possible therapies," said author Nicolas Lévy of the Faculté de Médecine de la Timone, (Inserm laboratory U491), and Hôpital d'enfants de la Timone in Marseille, France.
"Now that researchers in this field have the gene in hand, they can investigate what goes awry in the bodies of children with HGPS, and hopefully find ways to prevent or reverse those changes," said Stella Hurtley, a Science editor working in Cambridge, U.K.
Though Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease -- affecting one in an estimated four to eight million children, according to Lévy -- its effects are quite recognizable.
Baldness, aged-looking skin, dwarfism, and a small face and jaw relative to head size are outwardly visible characteristics of the disorder. Children with HGPS also have health problems typically associated with the elderly, including joint stiffness, hip dislocations, cardiovascular problems, and atherosclerosis. The children's mental growth is normal.
Children with HGPS die at the average age of 13. There is currently no cure for the disease.
The mutation Lévy and his colleagues discovered occurs in the LMNA gene, which contains the "blueprints" for constructing two proteins, called Lamin A and Lamin C. Together with Lamin B, these proteins are woven into a wallpaper-like meshwork, lining the inside of the membrane around the cell's nucleus.
During cell division, the membrane breaks up, allowing the nucleus to split in two. As new membranes form around each of the two nuclei, the lamins then reweave themselves back into new meshwork linings. Cells with defective lamin proteins divide improperly and die prematurely, impairing tissues' ability to regenerate.
Disorders caused by defective lamin proteins are collectively known as laminopathies. Most affect just one tissue type. When Lévy's team began their study, another group had just implicated the LMNA gene in a laminopathy called mandibulo-acral dysplasia phenotype, or MAD.
"I thought ok, we really have to look for mutations in lamin gene for progeria," Lévy said.
An important challenge will be to better understand the various tasks that the lamin proteins carry out, according to Lévy. MAD was the first laminopathy found to affect multiple tissue types, as progeria does. The mechanisms underlying the differences among laminopathies is a mystery.
"We don't know enough about how lamins function to think in terms of therapy yet. I think we'll do it in the next ten years, but it will be difficult," Lévy said.
The authors studied the DNA sequences of LMNA genes from patients affected with HGPS. They found just one abnormality, the substitution of a single DNA "letter," or "base," within a segment called exon 11.
Exons are the DNA segments that contain information for producing a particular protein. Within the gene, they are interspersed with segments called introns. Before a messenger molecule can carry a copy of the genetic instructions over to the cell's protein-construction site, a special splicing system chops out the molecule's introns, so that it delivers only a string of exons.
Lévy's team determined that the LMNA mutation seems to jar the splicing machinery, in such a way that the end of exon 11 is cut off. This leads to the production of abnormal Lamin A proteins, although it doesn't affect Lamin C proteins.
For some reason, which the authors don't understand yet, the mutation only leads to abnormal Lamin A production in some cells, but not all of them.
The mutation is a "dominant mutation," meaning that individuals who inherit a defective copy of the gene from either parent develop HGPS.
Lévy emphasized that further research on more HGPS patients is needed to determine all its possible causes.
"HGPS is an exceedingly rare disorder, and it's difficult to explore a lot of patients in our studies….This study has been performed on very few cases, so our findings needs further confirmation, of course," he said.
Lévy's coauthors are Annachiare De Sandre-Diovannoli, Pierre Cau, Claire Navarro, and Irène Boccaccio of Faculté de Médecine de la Timone, (Inserm laboratory U491), in Marseille, France; Rafaëlle Bernard at Hôpital Timone in Marseille, France; Jeanne Amiel, Stanislas Lyonnet, Arnold Munnich, and Martine Le Merrer at Hôpital Necker (Inserm U393) in Paris, France; and Colin L. Stewart at the National Cancer Institute in Frederick, MD. Pierre Cau is also at Hôpital Conception, in Marseille. The study was supported by Association Française contre les Myopathies.
The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society, and publisher of the journal, Science (www.sciencemag.org). AAAS was founded in 1848, and serves some 265 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of one million. The non-profit AAAS (www.aaas.org) is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, www.eurekalert.org, the premier science-news Web site, a service of AAAS.
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