Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rare disease's gene may illuminate major disorders

20.06.2006
OHSU discovery of gene behind iron accumulation in brain has implications for Parkinson's, Alzheimer's

Oregon Health & Science University researchers have identified the gene behind a group of rare, progressive childhood disorders caused by an abnormal buildup of iron in the brain.

Discovery of the PLA2G6 gene, whose mutated forms trigger several genetic disorders categorized as neuroaxonal dystrophies, could shed light on the nerve cell degeneration that leads to such neurological maladies as Parkinson's and Alzheimer's diseases, both known to be associated with brain iron accumulation.

"If you're a family with a kid with one of these diseases, the impact is clear, specific and personal," said Susan J. Hayflick, M.D., professor of molecular and medical genetics, pediatrics and neurology in the OHSU School of Medicine. But because it may heighten understanding of other, better-known neurological disorders, "To the general population, (the discovery) has a larger impact, and that's a significant benefit."

In a study published online June 18 in the journal Nature Genetics, Hayflick and an international team of geneticists describe PLA2G6's discovery using DNA from families with infantile neuroaxonal dystrophy, or INAD, and a related disorder known as neurodegeneration with brain iron accumulation, or NBIA.

In INAD, also known as Seitelberger disease, symptoms start by age 2 and worsen over time, and include loss of head control and the ability to sit, crawl or walk, as well as deteriorating vision and speech, according to the National Institute of Neurological Disorders and Stroke, a branch of the National Institutes of Health. Children with the disease die between ages 5 and 10.

NBIA, sometimes called Hallervorden-Spatz syndrome, manifests itself between the teen years and adulthood. Symptoms include involuntary muscle contractions, rigidity and spasms in the limbs, face and torso, as well as confusion, disorientation, seizures, stupor and dementia. Rapid deterioration, punctuated by stable periods, lasts one to two months, with the rate of progression correlating with the patient's age – the later the onset, the better the patient fares. There is no cure nor standard treatment for either disease, which are inherited in a recessive fashion, meaning that both parents must contribute a defective gene to make both copies in the child defective. Incidence is 1 in 500,000 to 1 million.

PLA2G6's discovery means a clinical test can be developed to help families determine their chances of passing the disorders to their children.

"That's a direct outcome of this work," Hayflick said. "There are families who literally are waiting to have this test. They've been waiting for years. To have the option of bringing a child into this world you know won't have to suffer like this is extraordinary for a parent who's been through this. Some of them have had multiple children with the disease."

The disorders are caused by a build-up of iron in the basal ganglia, a cluster of gray-matter tissue structures deep in the brain that control motor function. The iron accumulation causes the branch-like axons that transmit electrical impulses from the nerve cell body to its terminal to swell, interrupting the signal sent to other nerve cells nearby.

PLA2G6 is thought to encode an enzyme that breaks down lipids involved in the reconstruction of a cell's membrane following damage by light and other toxins. When the gene is mutated, lipid metabolism is altered and iron builds up, triggering disease.

"I studied our entire INAD patient population for mutations in this gene and found over 44 different changes in the gene which would lead to disease," said study co-author Shawn Westaway, Ph.D., research assistant professor of molecular and medical genetics at OHSU. Working with scientists at the University of Birmingham School of Medicine, United Kingdom, Hayflick and Westaway collected DNA from 30 to 40 families affected by the diseases and narrowed the search for the suspect gene to a 100-gene block of DNA on chromosome 22, the second smallest chromosome in humans that contains 500 to 800 genes. The team then looked for genes in the region whose function was suggestive of the symptoms and parts of the body affected by the diseases, and the search was further narrowed to 75 genes.

"You just start sequencing genes and compare healthy people to people with the disease," Hayflick said. "In people with the disease, you see changes that are clearly disease causing."

After scouring the 75 genes, "we finally found mutations in PLA2G6 in a large kindred with multiple generations of affected individuals, and in three other smaller families," Westaway said.

The chromosomes containing the mutations are then compared to almost 200 control chromosomes not affected by the disease. "The severity of the mutation is usually a very good clue that the gene has been found," she said. "That evidence is confirmed by continuing to find different, but severe, mutations in the same gene in new patients diagnosed with INAD, which we have done."

PLA2G6 is among 18 lipid-metabolizing genes in a protein family known as phospholipase A2 (PLA2), and INAD is the first inherited disorder associated with mutations in one of these genes. Its discovery "unequivocally" links PLA2 defects to neurodegeneration, researchers say, which is significant because similar lipid metabolism changes are seen in neurodegeneration associated with ischemia from stroke, spinal cord trauma, head injury and Alzheimer's disease, making this metabolic pathway a potential drug target.

In addition, iron is known to accumulate with age in brain regions attacked by Alzheimer's and Parkinson's diseases. "This is a common end effect of many neurodegenerative disorders," Hayflick said.

Jonathan Modie | EurekAlert!
Further information:
http://www.ohsu.edu/

More articles from Life Sciences:

nachricht Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung

nachricht A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Pulverizing electronic waste is green, clean -- and cold

22.03.2017 | Materials Sciences

Astronomers hazard a ride in a 'drifting carousel' to understand pulsating stars

22.03.2017 | Physics and Astronomy

New gel-like coating beefs up the performance of lithium-sulfur batteries

22.03.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>