Genetic variants of the NEK1 gene that cause the coded protein to lose its function seem to increase the odds of developing amyotrophic lateral sclerosis (ALS) by more than ninefold, with these patients significantly more likely to experience weakness in their hands as a first symptom, a study has found.
While more than 30 genes have been implicated in the onset and development of ALS, only a handful — including C9ORF72, SOD1, FUS, TARDBP, VCP, and TBK1 — have been clearly demonstrated to account for ALS cases.
The NEK1 gene is among the other genes whose role in disease is much less understood. It has been proposed that variants (differences in DNA sequences) in this gene result in a severe disruption in the Nek1 protein function, increasing the risk of ALS significantly.
Nek1 works to control cell division and repair DNA errors, and regulates the formation of cilia — projections from cells that sense the environment — and the function of mitochondria (the cells’ powerhouses).
However, the frequency of such loss-of-function (LOF) variants, their exact association with ALS, and the clinical features of patients carrying them, are not fully understood.
To find out, researchers at the National Yang‐Ming University School of Medicine, Taiwan, screened 325 ALS patients and 1,000 healthy individuals in Taiwan for NEK1 LOF variants.
Among ALS patients, 58 had mutations in the 17 most common ALS-related genes — not including NEK1 — and 39 had a family history of the disease. Most patients (43.1%) had their first symptoms in their upper limbs, including 31.1% in their hands, usually observed as difficulty with simple tasks like writing or buttoning a shirt.
Results showed that six patients (1.8%) had LOF variants of the NEK1 gene, and nine (2.8%) had rare missense variants, which are characterized by changes in a single nucleotide (DNA’s building blocks) in the gene’s sequence. Only two of these 15 patients had other mutations in known ALS genes.
As for healthy people, LOF variants were present in two individuals (0.2%), and 1.6% had missense variants.
The team found that LOF variants were significantly more frequent in patients than in controls, and that they increased the odds of having ALS by 9.4 times. Missense variants, however, did not increase the chances of having the condition.
An analysis of the clinical presentation of ALS in the six patients with LOF mutations in the NEK1 gene revealed that the condition presented as hand weakness in all patients, which contrasted with patients in the group without NEK1 LOF variants.
The disease progressed rapidly to upper and lower limb weakness in all patients, and most also reported a rapid decline in ability to perform daily tasks. Some patients also experienced speech and swallowing problems (bulbar disease), and half died of respiratory failure or cardiac arrest within four of years of ALS diagnosis.
The findings show that these LOF variants are frequent in Taiwanese ALS patients, with about 2% of cases being potentially attributed to these variants, and that these patients tend to have hand-onset disease.
“In conclusion, we identified six ALS patients with NEK1 LOF variants in 325 unrelated Taiwanese ALS patients. All the patients had a hand‐onset ALS with an onset age ranged from 52 to 64 years,” the researchers wrote.
“This study characterizes the genetic and phenotypic features of NEK1 LOF variants and underlines their pathogenic role in ALS,” they concluded.
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