Genetic Discovery in ALS

August 26, 2016

A genetic mutation suspected to be associated with amyotrophic lateral sclerosis risk has been confirmed through a large-scale research effort.

An international, large-scale research effort led to discovery of a new gene associated with the risk for amyotrophic lateral sclerosis (ALS). The results of this work were reported by Kenna and colleagues in Nature Genetics last month.1

The gene, NEK1, encodes the serine/threonine kinase NIMA (never in mitosis gene-A)-related kinase. It plays a role in formation of nonmotile primary cilium, mitochondrial membrane permeability, and DNA repair. Disruption of these processes is linked to neurological defects and diseases.

NEK1 was discovered through sophisticated analyses of a large number of ALS samples from US and European patients. First, the authors identified optimal parameters of the gene analysis and confirmed their validity by applying them to the genes known to be associated with ALS. Extending these parameters to all genes allowed them to identify NEK1, whose association with ALS has been previously suspected but never confirmed.

Association of NEK1 with the disease was confirmed through the use of alternate analysis parameters and data sets. Samples from 4 patients with ALS with a high degree of genetic relatedness from an isolated community in the Netherlands were analyzed, and p.Arg261His variant of NEK1 was detected in each of the patients. Two of the four patients were homozygous for p.Arg261His and two were heterozygous; however, the disease phenotype did not differ between the patients.

Overall, 120 nonsynonymous NEK1 variants were detected in samples from patients with ALS and controls. Effects of NEK1 variants on the risk of ALS were validated through replication analyses of sporadic ALS cases (n = 10,589) and independent control cohorts (n = 3362). These analyses confirmed the association of p.Arg26His and NEK1 loss-of-function variants with the disease. Larger sample sizes are needed to confirm the pathogenicity of other NEK1 variants.

p.Arg261His variant was more common than loss-of-function variants; both types of variants were more common in familial vs sporadic ALS. Overall, these risk variants were present in approximately 3% of European and European-American patients with ALS.

The importance of these findings reflects the scale of research efforts that produced them. The repository of ALS biosamples used in the study was established by Project MinE, an international effort to sequence the genomes of thousands of people with ALS. The US and European research groups joined forces in analyzing the samples to identify a single gene associated with ALS.

John Landers, PhD, one of the leading authors of the study, is currently developing a novel mouse model of ALS based on identified NEK1 variants.2 These models will help researchers to understand the effects of these variants in vivo and, ultimately, to develop new therapeutic strategies.

References:

1. Kenna KP, et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat Genet. 2016 Jul 25. [Epub ahead of print]

2. ALS Ice Bucket Challenge Donations Lead to Significant Gene Discovery [press release]. Washington, D.C.: July 25, 2016. http://www.alsa.org/news/media/press-releases/significant-gene-discovery-072516.html Accessed August 14, 2016.