Genetic mutations are associated with a wide range of disorders or medical conditions. According to ALS News Today, researchers sought to understand the underlying genetics associated with sporadic amyotrophic lateral sclerosis (ALS). Through this research, which evaluated data from 2,900 patients, 24 different rare TP73 gene mutations were linked to a potentially increased ALS risk. Interested in learning more? Take a look at the study findings published in Neurology.

Amyotrophic Lateral Sclerosis (ALS)

Also known as Lou Gehrig’s disease, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which causes brain and spinal cord nerve cell death. As these nerve cells die, patients lose the ability to voluntarily control their muscle movement. ALS can be sporadic (90-95% of diagnoses) or familial (5-10% of diagnoses). Altogether, ALS affects males slightly more than females and is most prevalent in white males between the ages of 60 and 69. Symptoms include:

• Frequent tripping and falling
• Difficulty performing tasks such as walking, holding objects, or maintaining posture
• Muscle weakness, pain, and cramping
• Difficulty speaking and swallowing
• Changes in speech (slurring, slowed speech)
• Psychological distress
• Inability to move muscles (affecting the entire body)

TP73 Gene

According to NCBI, the tumor protein p73 (TP73) gene:

encodes a member of the p53 family of transcription factors involved in cellular responses to stress and development. It maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and is thought to contain multiple tumor suppressor genes.

In this particular study, researchers sought to better understanding the underlying genetic processes which spur ALS development. Although 61% of sporadic ALS is thought to have genetic influences, doctors are only able to associate genetic mutations to around 17% of diagnoses. 

To begin, researchers sourced blood samples from 324 healthy controls and 87 patients with sporadic ALS. Through this, the research team determined that five of the patients with ALS (5.75%) had rare TP73 gene mutations. Next, researchers expanded their data and analysis to include around 2,900 patients with sporadic ALS. Ultimately, this highlighted 24 different TP73 mutations which prevented delta-N-p73, a protein produced by TP73, from binding to another protein (p53). Because the proteins were unable to bind, delta-N-p73 is unable to stop cell death from occurring. 

In zebrafish models, a missing TP73 gene prompted increased motor neuron death, which is often what is seen in patients with ALS. Similarly, using lab-grown muscle cells, the 24 mutations discovered through this research stopped cells from adequately maturing and instead caused them to die early. Thus, researchers now believe that exploring these mutations moving forward could help to increase ALS understanding while also discovering potential new treatment options.