Gene mutation gradually causes devastating effects on cellular structure and function in Hutchinson-Gilford progeria syndrome

A mutation of the gene for lamin A protein gradually causes devastating effects on cellular structure and function in Hutchinson-Gilford progeria syndrome, a rare, fatal genetic condition characterized by an appearance of accelerated aging in children.

A study on the lamin A gene mutation was published in this week’s Proceedings of the National Academy of Sciences.

“Although a rare disease, progeria has long been considered a model for studying the mechanisms responsible for normal aging,” said lead author Robert D. Goldman, Stephen Walter Ranson Professor and chair, cell and molecular biology at Northwestern University Feinberg School of Medicine.

Goldman, a noted expert on the cell’s nuclear architecture, explained that lamin A protein forms a structural scaffolding that is responsible for many aspects of nuclear structure, and it is involved in gene expression and DNA replication.

Earlier research found that progeria is caused by mutations of the lamin A gene. The PNAS study, by scientists from Northwestern University, the Progeria Research Foundation and the National Institutes of Health, used microscopic and molecular techniques to examine nuclear structural changes of cells from children with progeria.

The researchers found that as the progeria cells aged, there was a gradual increase in defects in the nuclear structure and function, reflecting an abnormal accumulation of the defective lamin A protein. Very similar changes were seen in the nuclei of normal human cells from both children and elderly persons treated with the mutated lamin A gene.

Goldman and colleagues believe that as progeria cells age and their nuclei become progressively more defective, 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 envelope plays a key role in Hutchinson-Gilford progeria syndrome,” said Francis S. Collins, M.D., one of the senior authors on the study and director of the National Human Genome Research Institute.

“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,” Collins said.

“The findings of this study are critical to further understanding the causes of progeria,” said Leslie Gordon, M.D., one of the authors 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.”

Gordon, whose son has progeria, was part of the team that isolated the progeria gene in 2002.

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 to 24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, delayed or absent tooth formation, stiffness of joints, hip dislocation and progressive atherosclerotic heart disease.

Children with progeria die at an average age of 13 from heart attack or stroke, the leading causes of death of Americans.

This study was supported by grants from the National Cancer Institute, the National Human Genome Research Institute and The Progeria Research Foundation.

For information on progeria, see www.progeriaresearch.org.