NEW YORK (GenomeWeb) – Researchers have linked loss-of-function mutations in the KIF5A gene to amyotrophic lateral sclerosis.
ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease that affects about 14,500 people in the US, according to the Centers for Disease Control and Prevention.
An international team of researchers led by John Lander of the University of Massachusetts Medical School and Bryan Traynor at the National Institute on Aging conducted a genome-wide association study of nearly 21,000 cases and 60,000 controls while simultaneously performing a rare variant burden analysis that compared more than 1,000 familial ALS cases and 19,000 controls. As they reported today in the journal Neuron, the researchers identified a novel gene, KIF5A, that is associated with ALS. KIF5A encodes a protein that regulates the flow of materials along nerve axons.
"Axons extend from the brain to the bottom of the spine, forming some of the longest single cellular pathways in the body," Traynor said in a statement. "KIF5A helps to move key proteins and organelles — specialized parts of cells — up and down that axonal transport system, controlling the engines for the nervous system's long-range cargo trucks. This mutation disrupts that system, causing the symptoms we see with ALS."
Mutations in KIF5A have previously been found to cause two other neurodegenerative diseases: hereditary spastic paraplegia type 10 (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). The researchers noted that the mutations in KIF5A they uncovered in ALS affect a different region of the KIF5A protein than the mutations linked to SPG10 and CMT2. Gene mutations affecting SOD1 and C9orf72, among others, have also been linked to ALS.
To search for additional ALS susceptibility loci, the researchers performed a GWAS of 12,663 people diagnosed with ALS and 53,439 controls. They then merged their cohort with a recently published one of 12,577 ALS cases and 23,475 controls.
The researchers' analysis of this group uncovered five loci previously linked to ALS — TNIP1, C9orf72, TBK1, UNC13A, and C21orf2 — that reached significance, as well as five SNPs in linkage disequilibrium. One of those SNPs led to a coding alteration in KIF5A.
Separately, the researchers conducted an exome-wide rare burden analysis that compared the frequency of variants within each gene in a case-control manner using 1,138 familial ALS cases and 19,494 controls. About 10 percent of ALS cases show a family history of disease, while the rest are sporadic.
The known ALS-linked genes TBK1 and NEK1 reached exome-wide significance in this analysis, but so did KIF5A. The researchers noted that six loss-of-function mutations in this gene were present among their cases. These variants could all be traced to a 34-base-pair region and were predicted to affect splicing and the C-terminus of the encoded protein.
Traynor and his colleagues then replicated the association of KIF5A with ALS in another cohort of 4,159 cases and 18,650 controls, but noted that they could not rule out other variants in LD. Screening for KIF5A mutations in a further 9,046 ALS cases uncovered three additional carriers.
The KIF5A mutations the researchers uncovered differed from those previously linked to disease in SPG10 and CMT2. The SPG10- and CMT2-linked variants are largely missense mutations that affect the N-terminal motor domain of the protein, while the ALS-linked variants mostly affect the C-terminal cargo-binding region of KIF5A.
Traynor and his colleagues also found that patients with KIF5A loss-of-function mutations had a median age of onset of 46.5 years, younger than usual, but also a median survival time of more than 10 years, longer than the typical survival time of 20 months to 36 months.
The implication of KIF5A in ALS underscores the involvement of the cytoskeleton in the disease, the researchers said. They further suggested that targeting the cytoskeleton could be a potential treatment approach.
Traynor added that the researchers would next be examining which intracellular transports are affected by the KIF5A mutations and how mutations affecting one end cause one disease, while mutations at the other are linked to another disease.