Navigation Links
Stanford researchers identify genetic suspects in sporadic Lou Gehrig's disease
Date:5/26/2013

STANFORD, Calif. - Researchers at the Stanford University School of Medicine have identified mutations in several new genes that might be associated with the development of spontaneously occurring cases of the neurodegenerative disease known as amyotrophic lateral sclerosis, or ALS. Also known as Lou Gehrig's disease, the progressive, fatal condition, in which the motor neurons that control movement and breathing gradually cease to function, has no cure.

Although researchers know of some mutations associated with inherited forms of ALS, the majority of patients have no family history of the disease, and there are few clues as to its cause. The Stanford researchers compared the DNA sequences of 47 patients who have the spontaneous form of the disease, known as sporadic ALS, with those of their unaffected parents. The goal was to identify new mutations that were present in the patient but not in either parent that may have contributed to disease development.

Several suspects are mutations in genes that encode chromatin regulators - cellular proteins that govern how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Protein members of one these chromatin-regulatory complexes have recently been shown to play roles in normal development and some forms of cancer.

"The more we know about the genetic causes of the disorder, the greater insight we will have as to possible therapeutic targets," said Aaron Gitler, PhD, associate professor of genetics. "Until now, researchers have primarily relied upon large families with many cases of inherited ALS and attempted to pinpoint genetic regions that seem to occur only in patients. But more than 90 percent of ALS cases are sporadic, and many of the genes involved in these cases are unknown."

Gitler is the senior author of the study, which will be published online May 26 in Nature Neuroscience. Postdoctoral scholar Alessandra Chesi, PhD, is the lead author. Gitler and Chesi collaborated with members of the laboratory of Gerald Crabtree, MD, professor of developmental biology and of pathology. Crabtree, a Howard Hughes Medical Institute investigator, is also a co-author of the study.

Chesi and Gitler combined deductive reasoning with recent advances in sequencing technology to conduct the work, which relied on the availability of genetic samples from not only ALS patients, but also the patients' unaffected parents. Such trios can be difficult to obtain for diseases like sporadic ALS that strike well into adulthood when a patient's parents may no longer be alive. Gitler and Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect these samples.

The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient's exome, but not in that of his or her parents', were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.

Focusing on just the exome, which is about 1 percent of the total amount of DNA in each human cell, vastly reduced the total amount of DNA that needed to be sequenced and allowed the researchers to achieve relatively high coverage (or repeated sequencing to ensure accuracy) of each sample.

"We wanted to find novel changes in the patients," Chesi said. "These represent a class of mutations called de novo mutations that likely occurred during the production of the parents' reproductive cells." As a result, these mutations would be carried in all the cells of patients, but not in their parents or siblings.

Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin - a proportion that is much higher than would have been expected by chance, according to Chesi.

Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree's laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.

"We found that, in one sporadic ALS case, the last nine amino acids of this protein are missing," Gitler said. "I knew that Gerald Crabtree's lab had been investigating SS18L1, so I asked him about it. In fact, they had already identified these amino acids as being very important to the function of the protein."

When the researchers expressed the mutant SS18L1 in motor neurons isolated from mouse embryos, they found the neurons were unable to extend and grow new dendrites as robustly as normal neurons in response to stimuli. They also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of familial, or inherited, ALS.

Although the results are intriguing, the researchers caution that more work is necessary to conclusively prove whether and how mutations in SS18L1 contribute to sporadic cases of ALS. But now they have an idea of where to look in other patients, without requiring the existence of patient and parent trios. They are planning to sequence SS18L1 and other candidates in an additional few thousand sporadic ALS cases.

"This is the first systematic analysis of ALS triads for the presence of de novo mutations," Chesi said. "Now we have a list of candidate genes we can pursue. We haven't proven that these mutations cause ALS, but we've shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites."


'/>"/>

Contact: Krista Conger
kristac@stanford.edu
650-725-5371
Stanford University Medical Center
Source:Eurekalert

Related medicine news :

1. Protein complex may play role in preventing many forms of cancer, Stanford study shows
2. Stanford study examines cost-effectiveness of helicopter transport of trauma victims
3. Stanford researchers turn skin cells directly into the cells that insulate neurons
4. Stanford study shows different brains have similar responses to music
5. Now hear this: Stanford researchers identify forerunners of inner-ear cells that enable hearing
6. Immune cells engineered in lab to resist HIV infection, Stanford study shows
7. Optogenetics illuminates pathways of motivation through brain, Stanford study shows
8. Stanford/Yale study gives insight into subtle genomic differences among our own cells
9. Mechanism found for destruction of key allergy-inducing complexes, Stanford researchers say
10. Stanford bioengineer Karl Deisseroth wins NIH Transformative Research Award
11. MBL and Stanford scientists receive 2012 Lasker Award for Basic Medical Research
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/24/2016)... ... 2016 , ... EB Medicine presented its first-ever “Issue of ... in Ponte Vedra Beach, FL. The awards honor the outstanding work of leading ... and Pediatric Emergency Medicine Practice. , “With this award, we recognize the efforts ...
(Date:6/24/2016)... ... 2016 , ... National recruitment firm Slone Partners is pleased to ... genomics experience, as Vice President of North American Capital Sales at HTG Molecular ... the sales team in the commercialization of the HTG EdgeSeq system and associated reagents ...
(Date:6/24/2016)... ... ... Finally, a bruise cream that really works. Originally designed to reduce ... post-surgical treatment plans of a variety of other procedures including, but not limited to, ... bruising and causes a rapid resolution of bruising and inflammatory changes compared to no ...
(Date:6/24/2016)... ... 24, 2016 , ... SpiritQuest Sedona Retreats, located in Arizona has re-located to ... vortex sites: Cathedral Rock, Airport Mesa, and Boynton Canyon. The new retreat center ... as well as the Sedona Rouge, both popular accommodations for SpiritQuest clients. The ...
(Date:6/23/2016)... ... 23, 2016 , ... vcfo, a consulting firm that provides ... announce the promotion of Mike Mackey to Regional Vice President of Southeast Texas. ... responsible for managing client projects and overseeing vcfo financial consultants in the Houston ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... June 24, 2016 According to ... Type (Standard Pen Needles, Safety Pen Needles), Needle Length ... Growth Hormone), Mode of Purchase (Retail, Non-Retail) - Trends ... report studies the market for the forecast period of ... USD 2.81 Billion by 2021 from USD 1.65 Billion ...
(Date:6/23/2016)... , June 23, 2016  MedSource announced ... as its e-clinical software solution of choice.  This ... best possible value to their clients by offering ... The preferred relationship establishes nowEDC as the EDC ... for MedSource,s full-service clients.  "nowEDC has long been ...
(Date:6/23/2016)... 23, 2016  In a startling report released today, National ... by lacking a comprehensive, proven plan to eliminate prescription opioid overdoses. ... of how states are tackling the worst drug crisis in recorded ... – Kentucky , New Mexico ... . Of the 28 failing states, three – Michigan ...
Breaking Medicine Technology: