BioWorld International Correspondent

LONDON - Researchers have identified a genetic variant that increases the risk of developing the degenerative neurological disease amyotrophic lateral sclerosis (ALS) by about 30 percent.

The variant is in a gene that encodes the enzyme dipeptidyl peptidase 6, or DPP6, but little currently is known about the normal function of the gene or how it is altered in people with ALS.

Michael van Es, neurology resident at the University Medical Center in Utrecht, The Netherlands, told BioWorld International: "Understanding which genes are involved in ALS is the first step in understanding the mechanism by which the motor neurons die in this disease. This discovery is therefore a starting point for functional research to understand more about which metabolic pathways are affected, and possibly, in the long term, even trying to design new drugs to treat this disease."

A report of the work appeared in the Dec. 16, 2007, issue of Nature Genetics, in a paper titled: "Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis."

Between one and three people in every 100,000 develop ALS, usually in their late 50s to early 60s. The first symptoms are muscle weakness, caused by the death of motor neurons.

The disease is progressive and ultimately spreads throughout the body, including the respiratory muscles. There is no treatment, and sufferers normally die within three years of onset.

A study of twins where one person had developed ALS suggested that 38 percent to 85 percent of the risk of the other twin's developing sporadic ALS is due to genetic factors.

ALS also occurs as a Mendelian disease in 5 percent to 10 percent of cases with an autosomal dominant pattern of disease inheritance. In approximately 20 percent of those familial cases, mutations in the SOD1 gene can be identified. Those SOD1 mutations also have been found in patients with sporadic ALS, also suggesting that genetics plays a role in causing that form of the disease.

Van Es, working with Leonard van den Berg, also at the University Medical Center Utrecht, and their colleagues decided to carry out a genomewide association scan on a large group of patients and controls, to see if they could find single nucleotide polymorphisms (SNPs) that occur more commonly in patients than in controls.

There are estimated to be more than 12 million common SNPs in the human genome, but because recombination generally takes place at particular "hotspots," many of the SNPs commonly are inherited together.

Researchers therefore can use a panel of SNPs (known as tags) to infer which groups of SNPs have been inherited by people with a particular disease and which by healthy controls.

The Dutch team's first scan involved 461 patients and 450 healthy controls, but produced no statistically significant results.

At about the same time, a U.S. group led by Bryan Traynor of the National Institute of Mental Health in Bethesda, Md., carried out a similar study, with similarly negative findings.

"After this, we decided to combine both datasets, and see what we would come up with. This approach paid off - the result was a list of 15 candidate SNPs," Van Es said.

The collaborators then decided to analyze those 15 SNPs in three further populations, from the Netherlands, Sweden and Belgium.

"This was when we found we had one big hit, van Es said. "When we combined all the populations, we found we had a very significant and very consistent result for DPP6. The variant in this gene increases the risk of getting ALS by a factor of 1.3." A group of researchers working in Ireland also has now replicated the finding, van Es said.

No one really knows what the protein product of DPP6 does. It is expressed almost exclusively in the central nervous system. In people, it is not found in the peripheral blood.

DPP6 is known to convert the precursors of neuropeptides to their active forms, and vice versa, and to affect the operation of potassium channels. Perhaps most interestingly, it has been shown to be upregulated in rats following spinal cord injury.

Van Es and his colleagues now are embarking on sequencing the DPP6 gene.

"We have identified this SNP, but it is only a tag SNP," he said. "Hopefully, we will be able to identify something else that will be different in the gene between cases and controls, and that will explain either differential expression or an altered form of the protein."

The researchers also are designing cell culture experiments that will allow them to explore what happens to motor neurons when the product of DPP6 is absent or present in greater quantities than usual.

"There are bound to be other genes out there that increase the risk of ALS," van Es concluded. "DPP6 is just one of the pieces of the puzzle, and there is a long way to go. But this is a start."

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