Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rare genomic mutations found in 10 families with early-onset, familial Alzheimer's disease

18.06.2013
Unique changes in DNA structure found in each family, affected genes important to neuronal function

Although a family history of Alzheimer's disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer's, accounting for about half of such cases.

Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in the Alzheimer's patients in each family.

The study was conducted as part of the Alzheimer's Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer's Fund and the National Institute of Mental Health (NIMH).

"We found that the Alzheimer's-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes," says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. "Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer's disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer's pathogenesis." Hooli is a research fellow in Neurology at Harvard Medical School.

Most studies searching for genes contributing to Alzheimer's risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer's disease. "These are the first new early-onset familial Alzheimer's disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer's mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease." Tanzi explains.

The investigators reviewed genomic data from two sources – the NIMH Alzheimer's Disease Genetics Initiative and the National Cell Repository for Alzheimer's Disease – and focused on 261 families with at least one member who developed Alzheimer's before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer's-associated CNVs, with different gene segments being affected in each family.

While none of the novel variants have previously been associated with Alzheimer's disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer's. Mutations in MAPT also cause frontotemporal dementia.

Hooli explains, "Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer's to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer's disease."

"In a broader sense," Tanzi adds, "the advent of affordable, advanced whole-genome sequencing will lead to the identification of novel, rare mutations that lead to many human disorders. In the future, diagnosis and prognosis may rely more on disease genetics than on traditional laboratory results and behavioral effects. If knowing the exact genetic causes of these disorders leads to more effective and efficient treatment strategies targeted to specific defects, the consequences of this approach would be enormous."

In addition to Tanzi, the Joseph P. and Rose F. Kennedy Professor of Neurology at HMS and senior author of the current report, co-authors are Kristina Mullin, MS, Maxwell A. Blumenthal, and Can Zhang, PhD, MGH Genetics and Aging Unit; Gayatry Mohapatra, PhD, MGH Molecular Pathology Unit; Zsolt M. Kovacs-Vajna, PhD, University of Brescia, Italy; Manuel Mattheisen, MD, Brigham and Women's Hospital; Christoph Lange, PhD, Harvard School of Public Health, and Lars Bertram, MD, Max-Planck Institute for Molecular Genetics, Berlin.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."

Mike Morrison | EurekAlert!
Further information:
http://www.massgeneral.org/

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>