Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCSD Researchers Discover Gene Able to Suppress Retrovirus Insertion Mutations

29.09.2003


A naturally occurring variation in an essential gene can suppress genetic mutations caused by retroviruses in mice, according to a new discovery by researchers at the University of California, San Diego (UCSD) School of Medicine.



Published in the September 28 online edition of Nature Genetics, and in the journal’s October issue, the study identified a novel change in mice in a gene called mRNA nuclear export factor 1 (Nxf1). This gene normally acts as part of the cell’s machinery for ensuring that only properly functioning genes are expressed, or turned on. Genes that have been disrupted by insertions of retroviruses often fail to pass this quality checkpoint.

The UCSD team demonstrated that the novel form of Nxf1 restored function to mutated genes by increasing the amount of normal product made by the mutated gene, and alleviated abnormalities in two very different mouse mutations.


“The properties of this gene could be used to engineer a system for controlling some mutations caused by retroviruses,” said the study’s senior author, Bruce Hamilton, Ph.D., UCSD assistant professor of medicine. “This could be particularly useful for creating mouse models of human disorders where loss of gene expression is a target of therapeutic efforts, but the dose-responsiveness required for functional recovery is unknown, such as in Fragile X syndrome and certain cancers.”

Nxf1 controls expression of genes at the level of exporting messenger RNA (mRNA) from the nucleus. mRNA is an intermediary step in the production of proteins. DNA in the nucleus is transcribed into RNA, which is processed and exported to the cytoplasm. This mRNA is then translated to make proteins. However, when a retrovirus invades a cell, it sometimes inserts a copy of itself into a gene of the host cell. As a result, the host gene may be poorly expressed and depending upon the gene and how it is affected, this can cause disease.

Hamilton noted that was what surprised his team was that a protein required for a late step in gene expression – export of mRNA from the nucleus – appears to influence earlier steps in gene expression, processing of the pre-mRNA. Although previous work by others has identified genes that modify mutations by increasing the amount of RNA being initiated, or changing the ability to express a mutated gene, the new findings are the first to identify suppression at a later stage, when the mutated gene has been activated, but before it can do damage.

In their experiments, the UCSD team began by investigating a gene called Modifier-of-vibrator-1 (Mvb1), which reduces the damaging characteristics of a neurological gene mutation called vibrator. The vibrator mutation is caused by insertion of a mouse retrovirus called IAP.

The researchers studied vibrator mice, which have severe tremors, progressive degeneration of the brain stem and spinal cord, and die early. However, the UCSD team found that vibrator mice carrying the mvb1 genes showed reduced tremor severity and survived to adulthood. The team showed the Mvb1 did this by raising the amount of normal RNA made from the mutant vibrator gene.

In further experiments, the researchers showed that Mbv1 also modifies an Eya1 mutation that is a mouse model of human branchiootorenal syndrome, which is also caused by an IAP retrovirus. Eya1 is a gene required for development of the inner ear and other structures. Mutations are characterized by hearing impairment, ear malformation, and in some cases, by kidney malfunction. Again, Mbv1 modified several of the Eya1 characteristics by increasing the expression of normal RNA made from the mutant gene.

Next, the team used sophisticated laboratory techniques called positional complementation to identify Mvb1, and to determine that it is part of the mRNA nuclear export factor Nxfl. The team further showed that the variation in Nxf1 that allows it to suppress retrovirus mutations is present in a large population of wild mice. Their findings also suggested that this variant form of the gene has evolved, under natural selection, to increase its frequency in the population.

In follow-up work, the Hamilton team is clarifying the biochemical mechanism and testing the range of mutations that can be suppressed. And, they hope to adapt Nxfl for broader use as a research tool.

This work was supported by grants from the National Institutes of Health and the Medical Research Service of the U.S. Department of Veterans Affairs.

The paper’s first author was Jennifer A. Floyd, B.A., UCSD Biomedical Sciences Graduate Program. Additional authors were David A. Gold, B.A., UCSD Biomedical Sciences Graduate Program; Dorothy Concepcion, B.A., Tiffany H. Poon, B.A., Erica J. Ward, M.S., UCSD Department of Medicine; Xiaobo Wang, M.D., Elizabeth Keithley, Ph.D., UCSD Division of Otolaryngology; Dan Chen, B.A., UCSD Molecular Pathology Graduate Program; Rick A. Friedman M.D., Ph.D. Steven B. Chinn, B.A., House Ear Institute, Los Angeles, CA; Hon-Tsen Yu, Ph.D., Department of Zoology, National Taiwan University; Kazuo Moriwaki, Ph.D., RIKEN Bioresource Center, Japan; and Toshihiko Shiroishi, Ph.D., Mammalian Genetics Laboratory, National Institute of Genetics, Japan.

Sue Pondrom | UCSD news
Further information:
http://health.ucsd.edu/news/2003/09_28_Hamilton.html

More articles from Life Sciences:

nachricht New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience

nachricht Wintering ducks connect isolated wetlands by dispersing plant seeds
22.02.2017 | Utrecht University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Positrons as a new tool for lithium ion battery research: Holes in the electrode

22.02.2017 | Power and Electrical Engineering

New insights into the information processing of motor neurons

22.02.2017 | Life Sciences

Healthy Hiking in Smart Socks

22.02.2017 | Innovative Products

VideoLinks
B2B-VideoLinks
More VideoLinks >>>