TP73 Is an Amyotrophic Lateral Sclerosis Candidate Risk Gene (S25.006)

Objective: To better understand amyotrophic lateral sclerosis (ALS) pathogenesis by identifying novel ALS candidate risk genes. Background: ALS is a fatal disease in which motor neurons progressively degenerate. Genetic factors are known to play a significant role in ALS pathogenesis. To date, more than 15 genes have been strongly linked to the development of ALS. However, these genes do not completely account for the heritability of the disease. Design/Methods: A VAAST and PHEVOR burden analysis was performed on exome sequence data from 87 University of Utah sporadic ALS (SALS) patients and 324 healthy individuals from the Simons Simplex Collection to identify ALS candidate risk genes. VAAST and PHEVOR identified genes with a higher number of deleterious nonsynonymous single nucleotide variants (nsSNVs) in cases compared to controls. Select candidate risk genes from this analysis were then modeled in zebrafish using CRISPR/Cas9 to determine their role in motor neuron survival. Results: TP73 , which encodes p73, was the second-ranked VAAST / PHEVOR gene with five rare (minor allele frequency TP73 . All 22 nsSNVs were predicted to be deleterious by MetaSVM. Zebrafish embryos were injected with Cas9 and CRISPR RNA targeted to tp73 to disrupt the gene. We found a significant reduction in the primary axon length and number of spinal motor neurons in tp73 mutants. Further, tp73 mutants had a significant increase in motor neuron apoptosis. Conclusions: TP73 variants likely to be deleterious exist in a substantial number of ALS patients. Further, loss of p73 negatively affects motor neuron development and survival. This evidence suggests TP73 is involved in ALS pathogenesis and broadens understanding of the disease. Study Supported by: Utah Neuroscience Initiative; Utah Genome Project; National Institutes of Health (NIH): TL1TR001066, R01GM059290, R01GM104390, R35GM118335, and R37NS033123; Target ALS. Disclosure: Dr. Downie has nothing to disclose. Dr. Gibson holds stock and/or stock options in Recursion Pharmaceuticals. Dr. Tsetsou has nothing to disclose. Dr. Keefe has nothing to disclose. Dr. Russell has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Bromberg has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Accordant Health Care. Dr. Murtaugh has nothing to disclose. Dr. Pulst has nothing to disclose. Dr. Bonkowsky has nothing to disclose. Dr. Jorde has nothing to disclose.