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To date, several pathogenic mutations have been reported, but due to the rarity and genetic complexity of CMS and difficult genotype\u2013phenotype correlations, the CHAT mutations, and their consequences are underexplored. In this study, we systematically sift through the available genetic data in search of previously unreported pathogenic mutations and use a dynamic in silico model to provide structural explanations for the pathogenicity of the reported deleterious and undetermined variants. Through rigorous multiparameter analyses, we conclude that mutations can affect CHAT through a variety of different mechanisms: by disrupting the secondary structure, by perturbing the P\u2010loop through long\u2010range allosteric interactions, by disrupting the domain connecting loop, and by affecting the phosphorylation process. This study provides the first dynamic look at how mutations affect the structure and catalytic activity in CHAT and highlights the need for further genomic research to better understand the pathology of CHAT.<\/jats:p>","DOI":"10.1002\/jcb.29913","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T04:40:00Z","timestamp":1614660000000},"page":"787-800","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A multidimensional computational exploration of congenital myasthenic syndrome causing mutations in human choline acetyltransferase"],"prefix":"10.1002","volume":"122","author":[{"given":"Matej","family":"Jane\u017ei\u010d","sequence":"first","affiliation":[{"name":"Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN Yokohama Kanagawa Japan"},{"name":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo, Kashiwa Chiba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalarickal V.","family":"Dileep","sequence":"additional","affiliation":[{"name":"Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN Yokohama Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-8045","authenticated-orcid":false,"given":"Kam Y. 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