Muscle Research and Gene Ontology: New standards for improved data integration.

BACKGROUND: The Gene Ontology Project provides structured controlled vocabularies for molecular biology that can be used for the functional annotation of genes and gene products. In a collaboration between the Gene Ontology (GO) Consortium and the muscle biology community, we have made large-scale additions to the GO biological process and cellular component ontologies. The main focus of this ontology development work concerns skeletal muscle, with specific consideration given to the processes of muscle contraction, plasticity, development, and regeneration, and to the sarcomere and membrane-delimited compartments. Our aims were to update the existing structure to reflect current knowledge, and to resolve, in an accommodating manner, the ambiguity in the language used by the community. RESULTS: The updated muscle terminologies have been incorporated into the GO. There are now 159 new terms covering critical research areas, and 57 existing terms have been improved and reorganized to follow their usage in muscle literature. CONCLUSION: The revised GO structure should improve the interpretation of data from high-throughput (e.g. microarray and proteomic) experiments in the area of muscle science and muscle disease. We actively encourage community feedback on, and gene product annotation with these new terms. Please visit the Muscle Community Annotation Wiki http://wiki.geneontology.org/index.php/Muscle_Biology

A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy

Background: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for 3c60% of ACM cases, but the remaining 40% is still genetically elusive. Objective: The purpose of this study was to identify the underlying genetic cause in probands with ACM. Methods: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes\u2014DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. Results: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed 651 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. Conclusion: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.Background: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for 3c60% of ACM cases, but the remaining 40% is still genetically elusive. Objective: The purpose of this study was to identify the underlying genetic cause in probands with ACM. Methods: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes\u2014DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. Results: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed 651 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. Conclusion: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined