Featured Research

from universities, journals, and other organizations

Progressive neurodegenerative disorder linked to R-loop formation

Date:
April 17, 2014
Source:
University of California - Davis Health System
Summary:
A new feature of the genetic mutation responsible for the progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome -- the formation of 'R-loops,' has been discovered. Researchers believe it may be associated with the disorder's neurological symptoms, such as tremors, lack of balance, features of Parkinsonism, and cognitive decline.

The finding suggests that the R-loops may be potential targets for drug development, said Paul Hagerman, senior study author, professor in the Department of Biochemistry and Molecular Medicine and director of the UC Davis NeuroTherapeutics Research Institute.
Credit: Image courtesy of University of California - Davis Health System

Researchers at UC Davis have identified a new feature of the genetic mutation responsible for the progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS) -- the formation of "R-loops," which they believe may be associated with the disorder's neurological symptoms, such as tremors, lack of balance, features of Parkinsonism, and cognitive decline.

The finding suggests that the R-loops may be potential targets for drug development, said Paul Hagerman, senior study author, professor in the Department of Biochemistry and Molecular Medicine and director of the UC Davis NeuroTherapeutics Research Institute. The study, "Transcription-associated R-loop Formation across the Human FMR1 CGG-repeat Region," is published in the online journal PLoS Genetics.

An R-loop is formed when the messenger RNA being made at the gene reinserts itself into the DNA helix, displacing one strand of DNA, which creates the "loop." Such loops are known to be prone to damage, which can in turn lead to loss of cell function, particularly in neurons.

Hagerman and his collaborators discovered the R-loops while investigating mutations in the gene that causes FXTAS and other conditions associated with the fragile X mental retardation gene 1 (FMR1). R-loops are not unique to FXTAS and can occur in the promoter regions of many genes.

"But in FXTAS, the R-loops are more numerous and much longer than they are in FMR1 genes that are not mutated," said Hagerman, a researcher who also is affiliated with the UC Davis MIND Institute. "

In FXTAS, the number of excessive CGG repeats and the length of the R-loops are correlated, Hagerman said.

"The longer the R-loops, the greater their likelihood of being damaged," he said.

Like other genes, FMR1 is composed of the molecules adenine, thymine, cytosine and guanine, commonly referred to by their abbreviations, A, C, G and T. In the promoter area of a mutated FMR1 gene a trio of these molecules, C-G-G, is repeated an excessive number of times. In healthy individuals without the FMR1 gene mutation, the total of C-G-G repeats ranges from six to 45. However, in patients with FXTAS, the number of C-G-G repeats can be 200 or more.

The excessive numbers of C-G-G repeats in the mutated FMR1 gene are so distinctive that they are the basis of a genetic test to determine whether a patient has FXTAS or one of the other fragile X-associated disorders caused by FMR1 mutations.

In addition to FXTAS, fragile X-associated disorders include fragile X syndrome, the most common form of intellectual disability in children, and fragile X-associated primary ovarian insufficiency (FXPOI). In fragile X syndrome, the number of C-C-G repeats exceeds 200. The FMR1 gene mutation in fragile X is regarded as "full mutation," while the mutation in FXTAS and FXPOI are referred to as "premutations," Hagerman said.

Although a higher than normal number of CGG repeats in the FMR1 gene characterizes both FXTAS and fragile X syndrome, the molecular mechanisms that are disrupted in these disorders differ substantially, he pointed out.

In patients with fragile X syndrome, the abnormally high number of C-G-G repeats shuts down, or silences, the FMRI gene. In FXTAS, the less dramatic increase in C-G-G repeats boost the gene's transcription of its DNA into overdrive, triggering the creation of excessively long R-loops that are toxic to neurons, he said.


Story Source:

The above story is based on materials provided by University of California - Davis Health System. Note: Materials may be edited for content and length.


Journal Reference:

  1. Erick W. Loomis, Lionel A. Sanz, Frιdιric Chιdin, Paul J. Hagerman. Transcription-Associated R-Loop Formation across the Human FMR1 CGG-Repeat Region. PLoS Genetics, 2014; 10 (4): e1004294 DOI: 10.1371/journal.pgen.1004294

Cite This Page:

University of California - Davis Health System. "Progressive neurodegenerative disorder linked to R-loop formation." ScienceDaily. ScienceDaily, 17 April 2014. <www.sciencedaily.com/releases/2014/04/140417191610.htm>.
University of California - Davis Health System. (2014, April 17). Progressive neurodegenerative disorder linked to R-loop formation. ScienceDaily. Retrieved September 22, 2014 from www.sciencedaily.com/releases/2014/04/140417191610.htm
University of California - Davis Health System. "Progressive neurodegenerative disorder linked to R-loop formation." ScienceDaily. www.sciencedaily.com/releases/2014/04/140417191610.htm (accessed September 22, 2014).

Share This



More Health & Medicine News

Monday, September 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Liberia Pleads for Help to Fight Ebola

Liberia Pleads for Help to Fight Ebola

AP (Sep. 22, 2014) — Liberia's finance minister is urging the international community to quickly follow through on pledges of cash to battle Ebola. Bodies are piling up in the capital Monrovia as the nation awaits more help. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Ebola Doctor Says Border Controls Critical

Ebola Doctor Says Border Controls Critical

AP (Sep. 22, 2014) — A Florida doctor who helped fight the expanding Ebola outbreak in West Africa says the disease can be stopped, but only if nations quickly step up their response and make border control a priority. (Sept. 22) Video provided by AP
Powered by NewsLook.com
Global Ebola Aid Increasing But Critics Say It's Late

Global Ebola Aid Increasing But Critics Say It's Late

Newsy (Sep. 21, 2014) — More than 100 tons of medical supplies were sent to West Africa on Saturday, but aid workers say the global response is still sluggish. Video provided by Newsy
Powered by NewsLook.com
Sierra Leone in Lockdown to Control Ebola

Sierra Leone in Lockdown to Control Ebola

AP (Sep. 21, 2014) — Sierra Leone residents remained in lockdown on Saturday as part of a massive effort to confine millions of people to their homes in a bid to stem the biggest Ebola outbreak in history. (Sept. 20) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins