Research highlight

Genetics: The mutations that cause familial ALS

Nature Neuroscience

March 25, 2015

Mutations in the TBK1 gene can cause familial amyotrophic lateral sclerosis (ALS), according to a study published this week in Nature Neuroscience. Familial ALS accounts for an estimated 10 percent of cases worldwide.

ALS, which is also known as Lou Gehrig’s disease or motor neuron disease, is a complex and currently untreatable neurodegenerative disorder that affects motor neurons and causes patients to lose muscle control throughout the body. ALS can lead to paralysis and sometimes death within three to five years after disease onset. Recent advances in DNA sequencing technology have allowed scientists to identify dozens of mutations in different genes that can cause the disease, but so far these genes account for less than a third of ALS cases.

Jochen Weishaupt and colleagues sequenced the exomes (protein coding DNA) of 252 patients with ALS who have a family history of the disease. They identified loss-of-function mutations in the gene TBK1 that were linked with the disease across generations and observed that disruption of just one copy of the gene was sufficient to cause ALS. These mutations were not found in healthy individuals or in an additional 1,010 individuals who developed ALS sporadically.

TBK1 encodes for a protein involved in inflammation and the clearing of cellular debris. It interacts with two other genes, OPTN and SQSTM1, involved in the same cellular processes, which are also known to cause ALS when mutated. This study adds TBK1 to a growing list of genes that cause ALS and helps identify common biological processes that may be involved in the development of the disease across different families.

doi: 10.1038/nn.4000

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