Gene mutation causes progressive changes to cell structure in children with Progeria

06/08/04

New study advances drive for treatment and cure for fatal rapid aging disease

[Boston, MA June 8, 2004] Researchers today announced that a mutation of the Lamin A gene gradually causes devastating effects on cellular structure and function in children with Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria). The study was published in this week's Proceedings of the National Academy of Sciences (PNAS). Progeria is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children.

"Although it is a rare disease, Progeria has long been considered to be a model for studying the mechanisms responsible for normal aging" said lead author Robert D. Goldman, Ph.D., Stephen Walter Ranson Professor and Chair, Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine. "This study highlights the importance of the Lamin A gene in the maintenance of cell structure and function."

In April 2003, a team of researchers assembled by The Progeria Research Foundation (PRF), and including the National Human Genome Research Institute (NHGRI), one of the 27 institutes and centers that make up the National Institutes of Health (NIH), announced the discovery of the gene that causes Progeria. That study, published in the April 16th 2003 issue of Nature, found that the disease is not inherited, but instead is caused by chance mutations to the LMNA gene (Lamin A). The Lamin A protein is the structural scaffolding that holds the nucleus together, and is involved in gene expression and DNA replication.

In the PNAS study, the result of a collaborative effort launched by researchers from Northwestern, The Progeria Research Foundation and NHGRI, microscopic and molecular techniques were used to examine the nuclear structure of cells from children with Progeria. As the Progeria cells aged, there was a gradual increase in defects in their nuclear structure and function, reflecting an abnormal accumulation of the defective Lamin A protein. Very similar changes were seen in normal human cells from both children and elderly persons treated with the defective Lamin A.

These researchers now believe that as Progeria cells age, there are significant changes in cell function that are directly attributable to the amount of mutant Lamin A protein.

"These findings strengthen our suspicions that instability of the cell's nuclear membrane plays a key role in Hutchinson-Gilford Progeria Syndrome. We now know far more about how one tiny, genetic mutation can lead to a situation in which the cell's architecture is severely and progressively damaged," said Dr. Francis Collins, Director of NHGRI and the study's senior author.

"The findings of this study are critical to further understanding the cause of heart disease and cellular aging in Progeria," said Leslie Gordon, M.D., Ph.D., study author and Medical Director of The Progeria Research Foundation. "We are optimistic that with every new study and discovery in the field of Progeria, we are one step closer to finding a cure."

About one in four to eight million newborns have Progeria and, although they are born looking healthy, they begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints and hip dislocation. All children with Progeria die at an average age of 13 from heart failure or stroke, the number 1 killer of all Americans.

Source: Eurekalert & others

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