University of Utah researchers will present the study at the American Academy of Neurology annual meeting in Los Angeles at 4:30 p.m. Pacific time on April 24. The title is “TP73 Is an Amyotrophic Lateral Sclerosis Candidate Risk Gene.” The study’s abstract was published in the journal Neurology.
ALS News Today will cover the convention, which runs from April 21-27.
The hallmark of ALS is the degeneration of movement nerve cells, which transmit signals to muscle cells, prompting muscles to contract or relax.
Five to 10 percent of ALS cases are inherited. The rest are sporadic — that is, they don’t run in families.
Genetic factors play a key role even in non-inherited cases by influencing a person’s susceptibility to ALS, however. In fact, more than 15 genes have been linked to the development of the non-inherited form of the disease.
A research team wondered if they could identify more genes that increase the risk of a person developing sporadic ALS.
They used a genetics testing approach called exome sequencing with 87 sporadic ALS patients and 324 healthy individuals. The exome is made up of exons, the gene components that generate proteins.
A key finding was that ALS patients had larger numbers of a genetic variation that can change a protein’s structure and function. The variation, called deleterious nonsynonymous single nucleotide variant, or nsSNV, alters the amino acid sequence in a protein.
One gene in particular was associated with this variation, researchers found. The TP73 gene of four sporadic ALS patients had five rare nsSNVs, they said.
The TP73 gene encodes for p73, a protein involved in movement nerve cell responses to development and stress.
Screening an additional 2,900 ALS patients led to the team identifying 24 rare variations of TP73. Gene analysis suggested that 22 of the 24 nsSNVs would increase a person’s susceptibility to disease.
Researchers used the information to disrupt the tp73 gene of zebrafish so they could study its role in movement nerve cell survival.
Using the CRISPR/Cas9 gene editing tool, they discovered that mutations of tp73 led to shorter nerve fibers, a lower number of movement nerve cells in the spinal cord, and a higher death rate of these cells.
Overall, the study showed that a significant number of ALS patients carry TP73 variations that could have increased their susceptibility to the disease and that could affect their movement nerve cell development and survival.
“This evidence suggests TP73 is involved in ALS pathogenesis [disease development] and broadens understanding of the disease,” the researchers wrote.