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Genomics Identifies Cause of Aging Disease in Children
By Nancy Touchette

Determining the cause of a rare disease that causes children to age rapidly and die young has been difficult because the disease arises sporadically and is not transmitted from generation to generation. But genomic technologies have helped two research teams pinpoint the cause of this devastating disease, known as Hutchinson-Gilford progeria syndrome.

A mutation in lamin A results in irregularities in nuclei (right) compared to those with the normal gene (left).

The disease arises from a mutation in the lamin A gene, which codes for two proteins that line the inner membrane of the nucleus. Both research teams identified the same mutation, which causes a defective version of the lamin A protein.

Progeria typically affects one in 8 million newborns throughout the world. Children with the disease age at a rate that is five to ten times greater than normal and develop characteristics typical of the elderly: aged-looking skin, hair loss, atherosclerosis, and cardiovascular disease. Patients typically die by age thirteen, often from a heart attack or stroke.

Researchers hope the discovery will lead to new clues in the normal aging process. They also plan to look for variants in people who live unusually long lives, to see if the gene plays a role in longevity.

Many genetic diseases are deciphered by tracking the inheritance of gene mutations through generations. But the mutation that causes progeria is dominant, arising anew in each generation and causing death before it can be passed on.

To find the gene mutation, researchers analyzed the genomes of 22 progeria patients but found no clues. They did discover, however, that two patients had a condition known as uniparental isodisomy. This means that both copies of chromosome 1 had come mostly from one parent.

“That was a clue that there was something on chromosome 1,” says W. Ted Brown of the New York State Institute for Basic Research in Staten Island, and a co-author of a study that appears in Nature.

Next, the researchers found that a small portion of chromosome 1 was missing in a third patient. The deletion was known to include approximately 70 genes, based on the recently completed human genome sequence. One of the genes in this region, lamin A, was an obvious candidate for progeria because mutations in the gene contribute to diseases such as muscular dystrophy, Charcot-Marie-Tooth disorder, and a type of cardiomyopathy.

The researchers then screened the lamin A gene for mutations in 20 progeria patients and found the same mutation in all but two patients: A single letter of DNA is changed among the gene’s 25,000 chemical letters.

The mutation in the lamin A gene alters the way the messenger RNA is spliced, or processed. As a consequence, a stretch of fifty amino acids is deleted from the resulting protein.

The lamins serve as structural components of the nucleus, where they line the nuclear envelope. Exactly how they contribute to premature aging is unknown, but affected individuals have irregularly shaped nuclei. The protein is thought to play a role in the disassembly of the nucleus during mitosis, or cell division.

A research team led by Francis Collins at the National Human Genome Research Institute in Bethesda, Maryland, published the paper in Nature. Nicolas Lévy of the French National Institute of Medical Research in Marseille and his collaborators published their data in Science.

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Erikkson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Published online in Nature (April 16, 2003).
De Sandre-Giovannoli, A. et al. Lamin A Truncation in Hutchinson-Gilford progeria. Published online in Science (April 17, 2003).

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