Exome Sequencing Links New Genes to Sporadic ALS

by Amy Madsen on Fri, 2013-05-31 12:00

Twenty-five new genetic mutations were found in people with sporadic ALS but not in their parents, supporting the role of genetic contribution in the noninherited form of the disease

Article Highlights:
  • Although scientists have made great strides in determining the causes of familial ALS (where there is a history of the disease in more than one family member), there is limited understanding of what causes sporadic ALS (ALS without a family history).
  • Now, a research team has found that "de novo" (arising for the first time rather than being inherited) mutations may play a role in the risk and development of sporadic ALS.
  • Using a technique called exome sequencing, the team identified 25 de novo mutations, five of which code for a class of proteins known as chromatin regulators. It is possible these mutations are connected to the development of the disease.
  • The identification of genes or combinations of genes that cause or contribute to ALS is expected to help scientists better understand the disease.

A team of researchers in the U.S. and Australia has shed new light on sporadic amyotrophic lateral sclerosis (ALS), finding that some people with the disorder have gene mutations that may be associated with ALS and that do not exist in either of their parents — so-called de novo mutations.

Taking a cue from several recent studies that found de novo mutations in people with autism, schizophrenia and congenital heart defects, the research team, led by Aaron Gitler at Stanford (Calif.) University School of Medicine, used a technique called exome sequencing to examine the DNA coding regions of 141 people — 47 people with sporadic ALS along with both of their unaffected parents.

The researchers identified 25 de novo mutations in the people with ALS — new mutations that were not present in either parent, and that may play a role in ALS.  Five of these mutations code for a class of proteins known as chromatin regulators that help turn genes on and off.

Although de novo mutations have been previously identified in people with sporadic ALS, these mutations were in genes associated with familial ALS (such as the SOD1 and FUS genes). The genes uncovered in this study have not been previously associated with the familial form of the disease.

The identification of genes or combinations of genes that cause or contribute to ALS can help scientists better understand the processes that are disrupted in the disease, and may point the way to biological targets around which therapies can be developed.

A potential role for 'CREST' gene in ALS

In further studies, the researchers focused on one of the five chromatin regulator genes called synovial sarcoma translocation gene on chromosome 18-like 1 (SS18L1), or calcium-responsive transactivator (CREST).

They transplanted mutated CREST genes into mouse nerve cell cultures and found that the resultant flawed CREST proteins were toxic, affecting the structure and function of mouse nerve cells.

In the presence of flawed CREST proteins, the cells developed abnormalities in branch-like parts of the cells called dendrites. Instead of developing long, branched dendrites, the cells grew shorter dendrites with fewer branches. Conversely, when normal CREST genes were inserted, dendrites developed absent of any defects.

The team also determined that CREST protein interacts with another protein, FUS, in nerve cells. Mutations in the FUS gene, which carries the genetic instructions for the FUS protein, are a known cause of familial ALS.

Additional studies are needed to corroborate the findings and assess the role of the identified genes in ALS.

The team published its findings online May 26, 2013, in Nature Neuroscience. To read the full report, for a fee, see: Exome Sequencing to Identify De Novo Mutations in Sporadic ALS Trios.

More about exome sequencing

Compared to previous generations of technology, exome sequencing is a faster and less expensive way to reveal the chemical “letters” that make up the human genome (DNA), and search for genes associated with human diseases.

As opposed to whole genome sequencing, in which a readout of an individual’s entire genome is produced, exome sequencing decodes only the stretches of DNA called exons, which contain instructions used in protein synthesis. (Introns, the DNA regions that do not contain information used to make proteins, are ignored.)

In February 2013, through its translational research program, MDA awarded a $400,000 grant to researchers in the National Institutes of Health (NIH) Laboratory of Neurogenetics to perform exome sequencing on samples taken from 1,000 people with sporadic ALS.

(The study discussed in this article is not connected to the MDA-NIH project; to read more about that project and to view a video about exome sequencing, see Unique ALS 'Exome-Sequencing' Project is Focus of New Grant.)

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