Mutations in the Gene for Muscle Protein Kinesin A Cause of Amyotrophic Lateral Sclerosis


As published in today’s issue of the journal Neuron, researchers have identified specific mutations in the kinesin family gene, KIF5A, that cause amyotrophic lateral sclerosis (ALS) (Neuron. 2018;97(6):1268-1283.e6.) Kinesin is an ATP-powered motor protein that moves vesicles and material within them from the neuronal cell body to the synapse along the microtubule cytoskeleton of the axon. Kinesin has three regions, the N-terminal domain, which binds to the microtubules; the C-terminal domain, which binds to vesicles being transported; and the linking domain, which connects the other two domains to one another. The KIF5A subtype is known to transport not only vesicles, but also mitochondria and neurotransmitter receptors, to the synapse; disruption in mitochondria transport is a known deficit in patients with ALS.

In a massive collaboration, led by John Landers, PhD and Bryan Traynor, MD, PhD, more than 250 researchers shared detailed genetic and clinical information from more than 80,000 subjects compare genetic data from ~21,000 patients with ALS to data from ~60,000 control subjects in a genome-wide association study. Rare variant analysis compared data from 1,138 people with familial ALS with data from 19,494 control subjects.

These analyses showed that a missense variant within the KIF5A gene has genome-wide significance for association with ALS risk. The mutation associated with ALS is in the C-terminal cargo-binding domain of KIF5A, and patients with loss-of-function mutation had an extended survival rate relative to typical ALS.  Interestingly, mutations in the N-terminal motor domain of KIF5A have previously been shown to be the cause of other neuromuscular diseases, Charcot-Marie-Tooth type 2 disease and hereditary spastic dysplasia. Although it is possible that other variants represent the causative risk factor, these results suggest that mutations in KIF5A may be a relatively common, but low-penetrance risk allele for ALS.

Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

"It was truly a pleasure to see the collaborative effort of so many groups coming together to help with our goal of identifying a novel ALS gene," said Dr. Landers. "It demonstrates that any single group may be able to make significant findings on its own but together we can accomplish boundless advances."

"This collaborative discovery of KIF5A gives greater insight into the cellular mechanisms that lead to motor neuron degeneration and identifies important new targets for future gene therapies," said Dr. Traynor.


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