Sci. Aging Knowl. Environ., 13 August 2003
Two premature aging syndromes previously considered distinct turn out to be connected
Key Words: progeroid helicase laminopathy alternative splicing amphipathic haploinsufficiency
Scientists thought that they understood the genetic underpinnings of Werner syndrome, a premature aging condition that usually strikes in early adulthood. But new work shows that a subset of patients diagnosed with the disease don't harbor the typical mutation but instead carry mutations in a gene that's linked to a different illness. The finding hints that the usual Werner-causing gene and its newly identified companion play a role in the same biochemical pathway, one that might influence the normal aging process.
In 1996, scientists discovered that Werner syndrome arises from defects in a gene called WRN that encodes a genome-repair enzyme (see Fry Review). But some Werner patients have normal WRN--and symptoms afflict many of these individuals unusually early. To explore these mysteries, Chen and colleagues investigated the possible involvement of LMNA, a gene that's associated with a more severe premature aging syndrome, Hutchinson-Gilford progeria syndrome (HGPS), that usually kills people by the early teens.
Out of 129 registered Werner syndrome cases, the researchers identified 26 that lack a mutation in WRN. Sequence analysis revealed LMNA mutations in four of the 26 patients.
LMNA encodes the proteins Lamin A and Lamin C, which support nuclear structure. LMNA defects cause a wide variety of maladies, including HGPS (see "Lamin-tation"). The "atypical" Werner syndrome patients didn't have the same mutation as HGPS patients do; their lesions were at the other end of the gene.
No known relation exists between the WRN and LMNA proteins. But according to W. Ted Brown, a medical geneticist at the Institute for Basic Research in Developmental Disabilities in New York City, the new finding should push scientists to search for one. Judith Campisi, a molecular biologist at Lawrence Berkeley National Laboratory in California, adds, "WRN and LMNA may be in a similar pathway that postpones age-related phenotypes." Perhaps, she suggests, LMNA influences the function of WRN; both reside in the nucleus and might interact physically with one another.
This study can only fan the flames of an already intense interest in LMNA. Hypothesizing that LMNA affects normal aging, the Cambridge, Massachusetts-based biotech firm Elixir Pharmaceuticals (see " 'Gero-Tech' Sprouts, But Will It Bloom?" and "Joining Forces") and its collaborators are seeking life-extending variants of the gene in centenarians. If defective LMNA causes a condition that resembles premature aging, the thinking goes, perhaps robust LMNA triggers the opposite. "It's a long shot, frankly," says Campisi, who's not involved in the project. "But it's a worthwhile thing to do."
By showing that premature aging syndromes overlap genetically, says biochemist Anthony Weiss of the University of Sydney in Australia, the research implies that mild forms of early aging that are not currently diagnosed as a disease might share some molecular bugs with Werner syndrome and HGPS. In addition, both Werner and HGPS patients frequently die from atherosclerosis; the genes involved might contribute to atherosclerosis in people who don't suffer from these ailments. Further study of LMNA could broaden our understanding of these conditions and lead to drugs that help not just patients with dramatic premature aging disorders but the rest of us too.
August 13, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150