Mutations in KIF5A Gene Linked to ALS in Large-Scale International Study

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by Alice Melão |

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Newly identified mutations in the KIF5A gene were recently found to contribute to amyotrophic lateral sclerosis (ALS), the result of a large-scale collaborative study involving more than 250 researchers from several of the world’s renowned ALS research labs.

John Landers, PhD, professor at the University of Massachusetts Medical School and Bryan Traynor, MD, PhD, senior investigator at the National Institute on Aging (NIA) at the National Institutes of Health (NIH), led the study, which was titled “Genome-wide Analyses Identify KIF5A as a Novel ALS Gene” and published in the journal Neuron.

The international research team conducted a genome-wide association study comparing the genetic code of 20,806 ALS patients with 59,804 healthy volunteers. Researchers also performed a rare variant burden analysis evaluating 1,138 cases of familial ALS and 19,494 controls. It is the largest such study of ALS to date.

“The extraordinary teamwork that went into this study underlines the value of global, collaborative science as we seek to better understand devastating diseases like ALS,” Richard J. Hodes, MD, director of NIA, said in a press release. “These types of collaborative data collection and analysis are important in identifying the pathways underlying disease and in developing approaches to treatment and prevention.”

The large-scale genetic analysis detected genes that had been previously associated with ALS, including TNIP1, C9orf72, TBK1, UNC13A, and C21orf2. In addition to these genes, researchers identified genetic mutations in the KIF5A, which were found to be strongly associated with ALS.

KIF5A has been previously linked to hereditary spastic paraparesis and Charcot-Marie-Tooth disease type 2 (CMT2), two rare neurodegenerative disorders with some symptoms similar to ALS. In contrast to the mutations connected to these disorders, those found in ALS patients were solely located in the terminal end of the gene.

Next, the team evaluated the clinical manifestations of the disease in patients with the newly identified KIF5A mutations, revealing that these patients were younger at ALS onset (46.5 years) compared with the mean age reported in epidemiological studies (65.2 years). These patients also exhibited longer disease duration, with a mean survival of about 117 months compared with the reported estimated time of 20 to 36 months.

“While this is unlikely to be a very common genetic cause for ALS, it identifies important new directions to explore possible future gene therapies,” Traynor said.

Researchers are planning to further evaluate the frequency and location of KIF5A mutations, as well as their contribution to ALS.