Characterization of ATP7B mutations causing Wilson Disease

Mohammed, Ameena (2022) Characterization of ATP7B mutations causing Wilson Disease. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Ameena Mohammed (17MS052)) 17MS052_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (24MB)

Abstract

Wilson disease is a rare monogenic disorder caused due to the mutations at the gene ATP7B affecting copper homeostasis. The disease is manifested with copper accumulation in the liver and brain, leading to potentially fatal hepatic, neurological and psychiatric symptoms. Over 600 mutations have been identified in ATP7B to cause WD. The frequency of the disease varies greatly with geographic locations, with a higher frequency of certain mutations in specific ethnic groups. The study attempts to characterize fifteen of such mutations chosen based on their location in the protein structure, clinical prevalence, and pathogenicity. The mutated protein structures were modeled, and the structural and functional consequences were attempted to be determined via insilico studies. The effect of mutations on properties such as stability of the so formed protein, its aggregation propensity, and pathogenicity was considered. An attempt has been made to model the altered interactions of the mutant ATP7B with one of its interacting partners,ATOX1. The study also presents a comprehensive data mining and metadata analysis to collate the clinically available information on the mutations and finally attempts to establish a genotypic phenotypic correlation of the two most prevalent mutations, H1069Q and R778L, from the copper-induced trafficking and copper transport assays previously done in the lab.

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