Sci. Aging Knowl. Environ., 23 April 2003
Vol. 2003, Issue 16, p. nw59
[DOI: 10.1126/sageke.2003.16.nw59]

NOTEWORTHY ARTICLES

Lamin-tation

Newly discovered mutation underlies rare premature aging disease

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/16/nw59

Key Words: laminopathy • splicing • dominant mutation • intermediate filament

A novel mutation acts like a fast-forward button, causing children with a rare disease to wither quickly, according to two new studies. The work pinpoints the genetic alteration responsible for the syndrome--opening new avenues for possible treatment--and raises the possibility that the affected protein plays a role in normal aging.

Children with Hutchinson-Gilford progeria syndrome (HGPS) appear to age prematurely, suffering from hair loss, skin deterioration, brittle bones, and atherosclerosis; most die of heart failure or stroke by their early teens (see "Of Hyperaging and Methuselah Genes"). The disease is genetic, and studies of affected families suggest that HGPS arises from newly generated mutations, rather than by inheritance. As a result, scientists have had trouble tracking down a DNA lesion that triggers the devastating disease. Previous studies led them to a large region of chromosome 1. This stretch includes a gene, LMNA, that encodes the proteins Lamin A and Lamin C, which form a mesh that supports the membrane around a cell's nucleus. Mutations in LMNA cause other diseases, including some with characteristics similar to those of HGPS, so two research teams combed the gene for changes connected with HGPS.

In a Nature study published online, Eriksson and colleagues found that 18 of 20 HGPS patients carried the same single base change in LMNA; the team also tested DNA from the parents of eight subjects and showed that none carried the mutation. De Sandre-Giovannoli and colleagues identified two affected individuals with the same change, according to work published online in Science; none of 300 unrelated, healthy people harbored the alteration. The mutation causes the gene to produce a Lamin A protein with a chunk missing from its middle. The truncation eliminates a sequence important for converting Lamin A into its functional form; mice unable to perform this protein processing step show signs of premature aging (see "Nuclear Fallout"). Additional studies by both groups reveal that cells from HGPS patients display misshapen nuclear membranes. Disrupting the lamin network might short-circuit signals that regulate genes, causing cells to malfunction, says developmental biologist Colin Stewart of the National Cancer Institute in Frederick, Maryland, a co-author of the Science paper.

"It's quite an achievement," says Anthony Weiss, a biochemist at the University of Sydney in Australia. The discovery points researchers toward potential treatments, he adds, and suggests that researchers should look for changes in Lamin A production during the normal aging process. The finding also provides an "absolutely essential diagnostic tool" that will enable physicians to determine whether a child has HGPS or a different disease, says progeria researcher Leslie Gordon of Tufts University School of Medicine in Boston, a co-author of the Nature study and the mother of a child with HGPS. Weiss says that he'd like to know how Lamin A proteins alter chromosome structure and gene expression, which might explain how a single mutation can manifest itself in so many different tissues but leave others unaffected. Armed with that knowledge, researchers might devise ways to restore lamin function and slow the deterioration of HGPS patients.

--R. John Davenport


April 23, 2003
  1. A. De Sandre-Giovannoli et al., Lamin A truncation in Hutchinson-Gilford progeria. Science, 17 April 2003 [e-pub ahead of print]. [Full Text]
  2. M. Eriksson et al., Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, week of 21 April 2003 [e-pub ahead of print]. [Abstract/Full Text] [The links will work when the article goes online.]
Citation: R. J. Davenport, Lamin-tation. Sci. SAGE KE 2003, nw59 (23 April 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/16/nw59








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