Variants in TP73 may have an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS), with these variants impairing the normal function of p73, causing increased apoptosis, and reducing the number of motor neurons in ALS, according to study results published in Neurology.

Previous studies have suggested genetic factors may contribute to up to 61% of sporadic ALS risk. TP73, which is part of the p53 family of tumor suppression transcription factors, has a role in the expression of genes that affect cell cycle arrest, apoptosis, and cellular differentiation.

In the current study, the researchers sought to identify novel risk loci for sporadic ALS. Next-generation sequencing and in vitro and in vivo experiments were used to assess the effect of various TP73 variations on protein function and the role of p73 protein in motor neuron health.


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The study sample included 87 patients with sporadic ALS treated at the University of Utah School of Medicine with available exome-sequencing results (discovery cohort), and 53 patients screened for TP73 variants (as part of the University of Utah H1K project). Exome-sequencing results of 324 control participants were included in the analysis. In addition, data were included on TP73 variants from a publicly available cohort of 2800 exome-sequenced patients with sporadic ALS (called the ALSdb cohort). The effects of TP73 variation were determined using in vitro and in vivo experiments.

Among 4 patients with sporadic ALS, 5 different heterozygous, rare, missense single-nucleotide variants in TP73 were identified. An additional TP73 missense single-nucleotide variant was identified in the cohort of 53 sequenced patients with ALS from the University of Utah. Further, 18 rare, nonsynonymous variants in TP73 were identified during additional screening in the ALSdb cohort.

All 22 single-nucleotide variants were predicted to be deleterious. Variants in TP73 caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance.

TP73 gives rise to 2 different main protein isoforms, TA-p73 and N-terminally truncated p73, which have opposing functions. A mouse neuroblastoma model showed that a TP73 variant inhibits binding of N-terminally truncated p73 to p53, illustrating that apoptotic pathways could have a more important function in ALS than previously thought. Furthermore, the model was useful in identifying p73 as an important factor in disease progression. While p73 expression levels increased as disease progressed, N-terminally truncated p73 expression was decreased.

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 knockout of TP73 in zebrafish was completed to assess motor neuron number and axon morphology. The researchers found that disruption of TP73 leads to a reduction in the number of spinal motor neurons and in axon branch length.

“These findings reveal unexpected aspects of ALS genetic risk and pathology and may identify new approaches to treatment,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures. 

Reference

Russell KL, Downie JM, Gibson SB, et al. Pathogenic effect of TP73 gene variants in people with amyotrophic lateral sclerosis. Neurology. 2021;97(3):e225-e235. doi:10.1212/WNL.0000000000012285



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