Genetic disease linked to protein build-up

August 29, 2012
Molecular biology: Genetic disease linked to protein build-up

Mutations of the gene Lmna previously thought to be directly responsible for a group of laminopathies—serious developmental conditions including premature aging and a form of muscular dystrophy—in fact cause them by allowing a critical protein to accumulate. An international collaborative group of researchers including Ya-Hui Chi and co-workers at the A*STAR Institute of Medical Biology have discovered in mice that reducing levels of the protein, Sun1, resulted in decreased severity of the diseases and longer life spans. This breakthrough finding may eventually lead to changes of the treatment strategy for developmental conditions.

The of the is strengthened by a meshwork of known collectively as the nuclear lamina. In mammals, the Lmna gene encodes two of the proteins that form the lamina filaments. Mice with two copies of dysfunctional Lmna genes model human Emery-Dreifuss muscular dystrophy (EDMD), and mice with genes incorporating a mutation that deletes 40 from the Lmna gene show features of the premature aging syndrome Hutchinson-Gilford progeria (HGPS). All these mice have misshapen cellular nuclei, degenerative tissues and organs, and short lives.

Recent research has shown that, as well as keeping the membrane in shape, the nuclear lamina is involved in activating genes, repairing DNA and organizing the nucleus. In order to investigate these roles, the researchers generated EDMD and HGPS model mice with genes encoding dysfunctional Sun1, a protein involved in linking the nuclear lamina and the cytoskeleton within the cell. To their surprise, these mice showed milder developmental defects and lived for longer.

In fact, cells from EDMD and HGPS model mice display an excessive accumulation of Sun1. The researchers found the same to be true of taken from those afflicted by HGPS. Their developmental problems were alleviated by lowering the level of Sun1. Further work suggested that the accumulation of Sun1 was the result not of increased production of the protein, but reduced degradation.

"Collectively the findings implicate Sun1 build-up as the common event of the disorders," says Chi. "We suspect that clinical trials and therapies that target the protein products of dysfunctional genes without resolving the Sun1 accumulation are ineffective or useless against HGPS. In fact, our experimental evidence shows that reduced metabolic turnover of Sun1 is a major cause of HGPS."

Chi and co-workers now want to investigate what factors interact with Sun1 for it to accumulate, and also if there are any other proteins responsible for HGPS.

Explore further: Scientists uncover exciting lead into premature ageing and heart disease

More information: Chen, C-Y., Chi, Y-H., Mutalif, R. A., Starost, M. F., Myers, T. G., et al. Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell 149, 565–577 (2012). Article

Related Stories

Scientists uncover exciting lead into premature ageing and heart disease

April 30, 2012
Scientists have discovered that they can dramatically increase the life span of mice with progeria (premature ageing disease) and heart disease (caused by Emery-Dreifuss muscular dystrophy) by reducing levels of a protein ...

Scientists create new genetic model of premature aging diseases

April 29, 2011
Working with a group of national and international researchers, scientists from the Florida campus of The Scripps Research Institute have developed a new genetic model of premature aging disorders that could shed light on ...

Rapamycin effective in mouse model of inherited heart disease and muscular dystrophies

July 25, 2012
Rapamycin, an immunosuppressant drug used in a variety of disease indications and under study in aging research labs around the world, improved function and extended survival in mice suffering from a genetic mutation which ...

Recommended for you

Estrogen discovery could shed new light on fertility problems

December 12, 2017
Estrogen produced in the brain is necessary for ovulation in monkeys, according to researchers at the University of Wisconsin-Madison who have upended the traditional understanding of the hormonal cascade that leads to release ...

Time of day affects severity of autoimmune disease

December 12, 2017
Insights into how the body clock and time of day influence immune responses are revealed today in a study published in leading international journal Nature Communications. Understanding the effect of the interplay between ...

3-D printed microfibers could provide structure for artificially grown body parts

December 12, 2017
Much as a frame provides structural support for a house and the chassis provides strength and shape for a car, a team of Penn State engineers believe they have a way to create the structural framework for growing living tissue ...

Potassium is critical to circadian rhythms in human red blood cells

December 12, 2017
An innovative new study from the University of Surrey and Cambridge's MRC Laboratory of Molecular Biology, published in the prestigious journal Nature Communications, has uncovered the secrets of the circadian rhythms in ...

Team identifies DNA element that may cause rare movement disorder

December 11, 2017
A team of Massachusetts General Hospital (MGH) researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism (XDP). Occurring only ...

Protein Daple coordinates single-cell and organ-wide directionality in the inner ear

December 11, 2017
Humans inherited the capacity to hear sounds thanks to structures that evolved millions of years ago. Sensory "hair cells" in the inner ear have the amazing ability to convert sound waves into electrical signals and transmit ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.