People with mutations in the gene coding for tumor protein p73 (TP73) are at higher risk of developing amyotrophic lateral sclerosis (ALS), researchers report.
Their study, “Loss of TP73 function contributes to amyotrophic lateral sclerosis pathogenesis,” was published online in bioRxiv.
There’s no doubt that some genes contribute to the disease mechanism of amyotrophic lateral sclerosis, as 68 percent of familial (hereditary) ALS and 17 percent of sporadic (without known cause) ALS cases have an identifiable genetic risk variant.
Importantly, evidence suggests that more than half of sporadic ALS risk is linked to genetic factors, indicating there are unknown harmful gene variants leading to the disease.
Investigators from the University of Utah School of Medicine analyzed the protein-coding regions of the genome of 87 sporadic ALS patients and 324 healthy subjects.
The team discovered that five patients had four distinct rare missense mutations in the TP73 gene, which encodes tumor protein 73 (p73). Of note, a missense mutation happens when an amino acid (a protein’s building block) is replaced by another, which changes a protein’s structure and may render it non-functional.
“In contrast, only three rare missense [mutations] in TP73” were found in the control group.
p73 belongs to the p53 family of transcription factors. It regulates the cellular response to DNA damage, cellular differentiation and death. Changes to the TP73 gene have been associated with brain abnormalities and motor dysfunction in mouse studies.
Researchers set out to investigate whether these rare and harmful p73 variants were also present in other study populations.
When analyzing the genome’s protein-coding regions of almost 2,900 patients, scientists observed 24 rare mutations in TP73 sequence.
Already-established scoring systems for mutations’ “harmfulness” revealed that most of the TP73 gene variants were deleterious.
Using mice muscle cells, scientists then tested whether these genetic changes impaired p73’s function. Results showed that the mutations changed the protein’s function.
“Next, we tested the effect of loss of p73 function on motor neuron development and [shape],” researchers stated.
To do so, the team used a gene editing tool known as CRISPR-Cas9. This technique allows scientists to edit parts of the genome by removing, adding, or altering specific sections of the DNA sequence.
They changed the TP73 gene sequence in zebrafish embryos and reported the animals had significantly fewer spinal motor neurons because of programmed cellular death signaling in comparison to control animals.
Results show the impact of abnormal p73 on spinal motor neuron development, which correlates with the disease mechanism of ALS.
In line with previous studies, mutant TP73 zebrafish embryos also had significant smaller spinal motor neuron fibers in the early stages of their development.
With this study, researchers show that changes to the coding sequence of p73 compromise motor neuron survival during development, similar to what happens in amyotrophic lateral sclerosis.
“Our data indicate that TP73 is a novel ALS risk gene. [Gene expression regulators] that drive neuronal cell survival, differentiation, and tumor suppressor pathways have not been previously implicated in ALS. These findings reveal unexpected aspects of the ALS genetic risk and pathology landscape and may open new approaches toward treatment,” researchers concluded.