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Exome Sequencing Uncovers ALS Risk Genes Related to Inflammation, Autophagy

NEW YORK (GenomeWeb) – A study appearing online today in Science has uncovered a new pathway that appears to contribute to the risk of amyotrophic lateral sclerosis (ALS).

By generating whole-exome sequences for thousands of individuals with or without ALS, researchers from Columbia University, the HudsonAlpha Institute for Biotechnology, Biogen Idec, and elsewhere narrowed in on mutations in genes with known roles in ALS — a set that included the optineurin-coding gene OPTN, which has been linked to familial forms of the degenerative motor neuron disease.

The team also detected alterations in genes not previously linked to ALS, including glitches in a kinase enzyme-coding gene called TBK1, and genes from related innate immune and autophagy pathways.

"Remarkably, the TBK1 protein and optineurin, which is encoded by the OPTN gene, interact physically and functionally," co-senior author David Goldstein, director of Columbia University's Institute for Genomic Medicine, said in a statement.

"Both proteins are required for the normal function of inflammatory and autophagy pathways, and now we have shown that mutations in either gene are associated with ALS," Goldstein explained. "Thus there seems to be no question that aberrations in the pathways that require TBK1 and OPTN are important in some ALS patients."

Past research has unearthed dozens of genes that may contribute to inherited forms of ALS, the team noted. Nevertheless, genes in that set tend to be altered in only a fraction of sporadic ALS cases, which are far more common.

In their search of genetic features to help in understanding, treating, and predicting ALS, the study's authors sequenced protein-coding portions of the genome in 2,874 individuals with ALS and 6,405 unaffected control individuals.

The team's analysis of the exome sequences revealed dozens of apparently pathogenic rare mutations in known ALS-related genes, as well as mutations in new ALS candidates that may warrant further investigation.

In particular, the researchers saw an over-representation of mutations affecting TBK1, which codes for an enzyme that phosphorylates proteins in inflammation and autophagy pathways. Their results suggest that alterations in TBK1 turn up in roughly 1 percent of ALS cases.

The team tended to see shorter-than-usual survival times in patients with glitches in TBK1 or in the D-amino acid oxidase enzyme-coding DAO. Meanwhile, individuals with mutations in multiple risk genes appeared to be diagnosed at younger ages than those with single risk gene mutations.

Moreover, the convergence of TBK1 OPTN on inflammatory and autophagy-related pathways has prompted researchers to look at these processes more closely in ALS, both in terms of understanding disease biology and uncovering potential treatment targets.

"These observations highlight a critical role of autophagy and/or inflammation in disease predisposition," Goldstein and his co-authors wrote.

"It is also noteworthy that many drugs have been developed that act on TBK1-mediated pathways owing to their role in tumor cell survival," they added, "and can therefore be used to investigate the effects of drug-dependent loss of function of the kinase."

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