Data from: Pathogenic effect of TP73 gene variants in people with amyotrophic lateral sclerosis

<p class="Paragraph"><b>Objective</b>: To identify novel disease associated loci for amyotrophic lateral sclerosis (ALS), we utilized sequencing data and performed <i>in vitro</i> and <i>in vivo</i> experiments to demonstrate pathogenicity of mutations identified in <i>TP73</i>.</p> <p class="Paragraph"><b>Methods</b>: We analyzed exome sequences of 87 sporadic ALS patients and 324 controls, with confirmatory sequencing in independent ALS cohorts of &gt;2,800 patients.  For the top hit, <i>TP73</i>, a regulator of apoptosis, differentiation, and a binding partner as well as homolog of the tumor suppressor gene <i>TP53,</i> we assayed mutation effects using <i>in vitro</i> and <i>in vivo</i> experiments.  C2C12 myoblast differentiation assays, characterization of myotube appearance, and immunoprecipitation of p53-p73 complexes were perform <i>in vitro</i>.  <i>In vivo</i>, we used CRISPR/Cas9 targeting of zebrafish <i>tp73</i> to assay motor neuron number and axon morphology.</p> <p class="Paragraph"><b>Results</b>: Four heterozygous rare, nonsynonymous mutations in <i>TP73</i> were identified in our sporadic ALS cohort. In independent ALS cohorts, we identified an additional 19 rare, deleterious variants in <i>TP73</i><i>.   </i>Patient <i>TP73</i> 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 <i>tp73</i> in zebrafish<i> </i>led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. </p> <p class="Paragraph"><b>Conclusion</b>: Together, these results strongly suggest that variants in <i>TP73 </i>correlate with risk for ALS and indicate a novel role for apoptosis in ALS disease pathology.</p>