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06.16.2021

Researchers identify new gene that may increase risk of amyotrophic lateral sclerosis

Researchers have identified a new gene that may increase a person's risk of developing amyotrophic lateral sclerosis, according to a new study published in the June 16, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The gene, called TP73, produces a protein to help regulate the life cycle of a cell. Researchers found that some people with amyotrophic lateral sclerosis have mutations in this gene and that the mutations may interfere with nerve cell health.

Amyotrophic lateral sclerosis is a rare, progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. People with amyotrophic lateral sclerosis lose the ability to initiate and control muscle movement, which often leads to total paralysis and death.

Both genetic and environmental factors can contribute to the development of amyotrophic lateral sclerosis. Approximately 15% of cases are diagnosed as familial amyotrophic lateral sclerosis, which is when a person has more than one family member who also had the disease. Cases with no known genetic cause are called sporadic amyotrophic lateral sclerosis.

"Much remains unknown about the genetics and processes that lead to the development of amyotrophic lateral sclerosis," said study author Lynn B Jorde PhD, of the University of Utah in Salt Lake City. "While known gene variants are critical determinants of 68% of familial amyotrophic lateral sclerosis cases, they only account for 17% of sporadic amyotrophic lateral sclerosis, yet up to 61% of sporadic amyotrophic lateral sclerosis is believed to be influenced by genetic factors. Our study has identified a new genetic risk factor for sporadic amyotrophic lateral sclerosis, rare mutations in the gene TP73. We also found that mutations of this gene have a damaging effect on protein function and that the protein created by this gene is necessary for nerve cell health."

For the study, 87 people with sporadic amyotrophic lateral sclerosis provided blood samples. Researchers used a technique called exome sequencing to examine the protein-coding genes for each participant. In this group, researchers found that 5 people had rare mutations in the TP73 gene.

Researchers then looked at 2 additional groups with sporadic amyotrophic lateral sclerosis, totaling nearly 2,900 people, and found an additional 19 people with rare mutations in the TP73 gene.

When researchers looked at the genes of a control group of 324 people without amyotrophic lateral sclerosis, they found no mutations in TP73.

In the lab, researchers did additional experiments on cells and found when there were mutations of the TP73 gene, it led to abnormal cell differentiation and increased cell death. They also used CRISPR gene editing technology to remove the TP73 gene and found it led to impaired development of nerve cells, similar to what is seen in amyotrophic lateral sclerosis.

"Together, our results strongly suggest that mutations in the gene TP73 increase the risk of amyotrophic lateral sclerosis," said Jorde. "Our research indicates that cell death linked to these mutations may be factor in the development of amyotrophic lateral sclerosis. This discovery provides a new target for researchers working to develop therapies to slow or even stop the progression of amyotrophic lateral sclerosis."

The study was supported by the National Institutes of Health and Target amyotrophic lateral sclerosis.

Source: News Release
American Academy of Neurology
June 16, 2021

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