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Newly Discovered Genetic Mutations May Increase Risk for Lou Gehrig’s Disease

Author: Doug Dollemore

ALS researchers Lynn Jorde and Kristi Russell on stairway

Newly detected genetic mutations could increase a person’s risk of developing ALS, according to University of Utah Health researchers Lynn Jorde (left) and Kristi Russell. Photo credit: Dave Titensor

During his 17-year career with the New York Yankees, Lou Gehrig was famed for his prowess as a hitter and for his durability on the baseball field, which earned him his nickname "The Iron Horse.” Then, mysteriously, in 1938, his iron body began to figuratively rust. He couldn’t run, hit, or field his position as well as he once did. When doctors finally diagnosed his condition, the news was devastating.

Gehrig had amyotrophic lateral sclerosis (ALS), a rare progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. People who have ALS gradually lose their ability to control muscle movement. Eventually, the condition, now often referred to as Lou Gehrig’s disease, leads to total paralysis and death. Then, as now, there is no cure.

In the 80 years since Gehrig’s death at age 37, scientists have sought to unravel what causes the disease and develop better treatments for it.

In the latest advance, University of Utah Health researchers have detected a set of genetic mutations that appear to increase a person’s risk of developing ALS. They say the discovery of mutations in TP73, a gene that has never been associated with ALS before, could help scientists develop new therapies to slow or even stop the progression of the disease.

“It’s really a novel discovery that suggests a very different pathway for the onset of at least some cases of ALS that hasn’t been explored before,” says Lynn Jorde, Ph.D., chair of the Department of Human Genetics at U of U Health and the senior author of the study. “From a scientific standpoint, it’s going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences.”

The study appears in Neurology, the medical journal of the American Academy of Neurology.

"From a scientific standpoint, it’s going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences."

About 85% of ALS cases are sporadic, meaning that no one in a patient’s family has a history of the disease. However, researchers suspect that up to 61% of sporadic ALS cases are influenced by genetic factors. But detecting those factors has been challenging.

“In the past, it has been difficult to determine ALS-causing genes because only recently has sequencing technology advanced enough to feasibly sequence many patients,” says Kristi L. Russell, a graduate research assistant at U of U Health and lead author of the study. “Additionally, many mutations in a single patient could be considered deleterious, so one must test the candidate mutations in animal models or cell culture, an incredibly time-consuming process.”

For this study, Jorde, Russell, and colleagues analyzed blood samples provided by 87 people with sporadic ALS who were being treated at U of U Health. Using a technique called exome sequencing, which zeroes in on the protein-coding regions within genes, they found five people who had rare, deleterious mutations in the TP73 gene, which plays a key role in apoptosis or programmed cell death. Then, the researchers studied data from 2,900 other sporadic ALS patients from the Utah Heritage 1K Project and the ALSdb cohort. Within these groups, they identified 24 different, rare protein-coding variants in TP73.

When the researchers did a similar analysis among 324 people who did not have ALS, the patient mutations in TP73 were not present.

In subsequent laboratory studies, knocking out or disabling TP73 in zebrafish impaired the development of nerve cells in a way that mimicked what appears to occur in ALS. Like in ALS, the zebrafish had fewer motor neurons and shorter axons, nerve fibers that transmit electrical impulses from neurons to muscle cells. This shortening could impede the axon’s ability to transmit impulses. Shorter axons transmit these impulses far less efficiently.

During their experiments, the researchers also found evidence that mutant TP73, which normally inhibits apoptosis in motor neurons, doesn’t work properly. As a result, they suspect that apoptosis is more likely to occur.

“It seems that mutant TP73 disrupts apoptosis, which leads to more neuronal death,” Russell says. “Many biological pathways have been implicated in ALS progression, but our study highlights the underappreciated role of apoptosis in ALS pathology. Apoptosis could potentially become a new focus or target for treatment drug screens.”