PUBLICATION
Pathogenic effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis
- Authors
- Russell, K.L., Downie, J.M., Gibson, S.B., Tsetsou, S., Keefe, M.D., Duran, J.A., Figueroa, K.P., Bromberg, M.B., Murtaugh, L.C., Bonkowsky, J.L., Pulst, S.M., Jorde, L.B.
- ID
- ZDB-PUB-210622-4
- Date
- 2021
- Source
- Neurology 97(3): e225-e235 (Journal)
- Registered Authors
- Bonkowsky, Joshua
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 34135078 Full text @ Neurology
Citation
Russell, K.L., Downie, J.M., Gibson, S.B., Tsetsou, S., Keefe, M.D., Duran, J.A., Figueroa, K.P., Bromberg, M.B., Murtaugh, L.C., Bonkowsky, J.L., Pulst, S.M., Jorde, L.B. (2021) Pathogenic effect of TP73 Gene Variants in People With Amyotrophic Lateral Sclerosis. Neurology. 97(3):e225-e235.
Abstract
Objective To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we utilized sequencing data and performed in vitro and in vivo experiments to demonstrate pathogenicity of mutations identified in TP73.
Methods We analyzed exome sequences of 87 sporadic ALS patients and 324 controls, with confirmatory sequencing in independent ALS cohorts of >2,800 patients. For the top hit, TP73, a regulator of apoptosis, differentiation, and a binding partner as well as homolog of the tumor suppressor gene TP53, we assayed mutation effects using in vitro and in vivo experiments. C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were perform in vitro. In vivo, we used CRISPR/Cas9 targeting of zebrafish tp73 to assay motor neuron number and axon morphology.
Results Five heterozygous rare, nonsynonymous mutations in TP73 were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in TP73. Patient TP73 mutations caused abnormal differentiation and increased apoptosis in the myoblast differentiation assay, with abnormal myotube appearance. Immunoprecipitation of mutant ΔN-p73 demonstrated that patient mutations hinder ΔN-p73's ability to bind p53. CRISPR/Cas9 knockout of tp73 in zebrafish led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology.
Conclusion Together, these results strongly suggest that variants in TP73 correlate with risk for ALS and indicate a novel role for apoptosis in ALS disease pathology.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping